The DOI matches its Crossref record; 194 of the 194 references it cites were found in a registry or an index; none of the 147 sources its claims cite is checked for support yet.
COVID-19 and the human innate immune system
Open accessAbstract
The introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the human population represents a tremendous medical and economic crisis. Innate immunity-as the first line of defense of our immune system-plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for coronavirus disease 2019 (COVID-19), the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which so far are lagging behind.
Overview
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Written from the paper’s full text.
TL;DR
This review proposes a conceptual framework for how the human innate immune system interacts with SARS-CoV-2 and argues that host innate variability, especially in type I interferon responses, is a major driver of heterogeneous COVID-19 courses. It synthesizes first-year pandemic evidence and calls for causal, longitudinal studies to guide stratification and therapy.
Key findings
- Disease heterogeneity is attributed mainly to host and environmental factors rather than viral genetics; 10%–20% of symptomatic patients develop severe or critical disease, while mutations such as D614G increase infectivity but do not explain the broad clinical spectrum.
- Type I interferon immunity is central: SARS-CoV-2 antagonizes it at multiple points, and severe COVID-19 has been linked to loss-of-function variants in TLR3, IRF7, and IRF9 pathways in an estimated 3.5% of severe cases, autoantibodies against type I interferons in more than 10% of severe cases, and X-chromosomal TLR7 variants in young ICU patients.
- Severe disease involves an early transient interferon/ISG wave followed by hyperinflammation with elevated IL-6, TNF, and other mediators, alongside immunosuppressive myeloid changes such as HLA-DRlo monocytes, PD-L1-expressing neutrophils, emergency myelopoiesis, and neutrophil extracellular trap formation; the “cytokine storm” label is debated, with viral sepsis proposed as an alternative description.
- Age and inflammaging are major risk factors, and a chromosome 3 risk locus inherited from Neanderthals is carried by about 50% of people in South Asia and about 16% in Europe; trained immunity via BCG is under investigation, with 21 BCG trials and 3 VPM1002 trials registered as of early 2021.
Methods
- Narrative/conceptual review rather than primary research; it integrates clinical observations, genetic association and sequencing studies, single-cell omics, proteomics, and animal-model findings from the first year of the pandemic.
- The authors organize the discussion around a five-phase disease trajectory and a systems-medicine framework linking clinical investigation, computational modeling, and experimental validation.
- No systematic search strategy, meta-analysis, or new patient cohort is described.
Limitations
- The authors state that causality of events is still lagging behind and that larger longitudinal and mechanistic studies are urgently needed; many cited findings are preliminary or correlative.
- Evident from the text: the review covers mainly early-pandemic literature, does not perform a formal quality assessment, and notes that therapeutic conclusions await results from ongoing randomized trials.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 147 cited sources checked · 0 supported · 0 flagged
In the paper
“Although many mutations decreased infectivity, the virus variant D614G in the spike protein of SARS-CoV-2 increased infectivity (Li et al., 2020).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Li et al., 2020
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“This is in stark contrast to the 2009 influenza pandemic, which had much lower incidence rates in the elderly population, indicating partial protection on population level due to earlier exposure to similar influenza viruses (Xu et al., 2010).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Xu et al., 2010
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“It is possible that cross-protection via adaptive immune responses against endemic coronaviruses might be in part responsible for mild disease courses in younger individuals (Lipsitch et al., 2020).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Lipsitch et al., 2020 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Similar to SARS-CoV (Matsuyama et al., 2010), SARS-CoV-2 employs the cellular serine protease TMPRSS2 for S protein priming.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Matsuyama et al., 2010 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Here, it was even possible to predict the impact of clinical risk factors such as sex, age, and smoking history among others on gene expression level of genes associated with viral entry.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Muus et al., 2021
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“In the lung, ACE2 and TMPRSS2 expression has been mainly identified in alveolar epithelial type II cells (Qi et al., 2020; Zou et al., 2020).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Qi et al., 2020
- Not checked yetcites Zou et al., 2020 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“co-infection of monocytes in the BALF with human metapneumovirus was identified in one of the severe COVID-19 patients (Bost et al., 2020)”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Bost et al., 2020 source
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“The strongest enrichment of viral RNA was observed in ciliated and epithelial progenitors.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Bost et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Viral RNA was also detected in a subset of macrophages (SPP1 + macrophages) (Bost et al., 2020; Chua et al., 2020).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“the angiotensin-converting enzyme 2 (ACE2), was also a major cellular entry point for SARS-CoV-2 (Hoffmann et al., 2020).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Hoffmann et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 53
- Probably not a substantial claim. 9
- The quote only partly states this claim. 4
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Innate immunity—as the first line of defense of our immune system—plays a central role in combating this novel virus.”
§ COVID-19 and the human innate immune system > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Disease courses range from mainly asymptomatic and mild courses to more severe and critical courses in 10%–20% of symptomatic patients who are at considerable risk of fatality with many different organ systems involved in differing combinations and with variable symptoms (Gupta et al., 2020)”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Gupta et al., 2020 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“TMPRSS2 is more widely expressed than ACE2, and cells with simultaneous expression were identified in the respiratory tree, the cornea, esophagus, ileum, colon, gallbladder, and common bile duct (Sungnak et al., 2020), yet there was no evidence for simultaneous expression in immune cells.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Sungnak et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Disease severity and mortality rates are significantly higher in elderly populations pointing toward lack of widespread long-lasting pre-existing adaptive immunity by T or B cells against SARS-CoV-2 (Morens and Fauci, 2020).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Morens and Fauci, 2020
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In vitro monocyte-derived macrophages and dendritic cells (DCs) are susceptible to SARS-CoV-2 infection, which is abortive, because these cells do not support virus replication (Yang et al., 2020a).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Yang et al., 2020a
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The virus itself, the environment, and the host can contribute to such disease heterogeneity (Morens and Fauci, 2020).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Morens and Fauci, 2020
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Numerous mutations identified so far by thousands of viral sequences obtained during the first 9 months of the pandemic (Candido et al., 2020; Oude Munnink et al., 2020) suggest that viral genetic diversity, genetic evolution, variable infectivity, or co-pathogenesis might contribute to infectivity and fatality, but not so much to disease heterogeneity observed for COVID-19.”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“An interesting observation of this study was the high co-expression of genes involved in early steps of antiviral immune responses in these epithelial cells, which indicated the potential for these specialized nasal cells to play an important role in the initial viral infection, spread, but potentially also, clearance.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Sungnak et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Although there is evidence that environmental factors such as seasonality, other natural disasters, environmental degradation, quality of the public health infrastructure, or governance by state authorities have an impact on overall disease burden for society (Han et al., 2020)”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
- Not checked yetcites Han et al., 2020 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“DeltaACE2 neither binds the SARS-CoV-2 spike protein nor serves as a carboxypeptidase.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Onabajo et al., 2020 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, there has been no evidence for the role of innate immune cells in SARS-CoV-2 gaining access to the retina (de Figueiredo et al., 2020) or the brain (Song et al., 2021), albeit the virus has been found in both organs.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the host itself seems to be the major factor explaining disease severity, infection rates (Merad and Martin, 2020; Vabret et al., 2020), and long-term medical consequences (Marshall, 2020).”
§ COVID-19 and the human innate immune system > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Similarly, the human placenta is highly susceptible to SARS-CoV-2 infection, but only non-immune cells including syncytiotrophoblasts in the first trimester and extravillous trophoblasts in the second trimester express ACE2 and TMPRSS2 and have been identified as cellular targets for the virus (Ashary et al., 2020).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Ashary et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“An interesting finding is the expression of ACE2 and TMPRSS2 on platelets, considering that patients present with signs of platelet hyperactivation, particularly in severe COVID-19 (Zhang et al., 2020b).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Zhang et al., 2020b
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The dynamics of type I IFNs in severe patients is in line with findings in a murine model of SARS-CoV-2 infection illustrating that type I IFNs do not control SARS-CoV-2 replication in vivo but are significant drivers of pathologic responses (Israelow et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Israelow et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Functional testing further supported the counteracting activity of ORF3b, ORF6, NSP1, or NSP13 on type I IFN activation, of which particularly ORF6 suppressed STAT1 and STAT2 phosphorylation and STAT1 nuclear translocation, (Konno et al., 2020; Lei et al., 2020; Xia et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“A longitudinal analysis confirmed an early peak with subsequent decline of IFNα and IFNλ in mild-to-moderate COVID-19, whereas levels further increased particularly during the second week in severe patients (Lucas et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Lucas et al., 2020 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“CD147 is widely expressed and receptor expression and viral load does not seem to correlate (Bost et al., 2020) arguing against CD147 as a major entry receptor for SARS-CoV-2.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Bost et al., 2020 source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In vitro exposure to SARS-CoV-2 or its Spike protein potentiated platelet aggregation, release of dense granules, upregulation of activation markers (PAC-1, CD62P), platelet spreading, and clot retraction.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Zhang et al., 2020b
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Interestingly, other coronavirus family member receptors (ANPEP and DPP4) and several proteases (CTSL, CTSB, and Furin) are uniformly expressed within the placenta throughout the first and second trimester, and genes necessary for viral budding and replication were also identified, strongly suggesting that the placenta is a vulnerable target for productive infection (Ashary et al., 2020).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
- Not checked yetcites Ashary et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“A common pattern of cell entry via endocytosis following receptor binding was established for coronaviruses, which is followed by viral RNA release into the cytoplasm, production of viral proteins, and formation of viral replication/transcription complexes on double-membrane vesicles (Snijder et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Snijder et al., 2020 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SARS-CoV-2-derived non-structural protein 16 (NSP16) suppresses global mRNA splicing and diminishes recognition of viral RNA by intracellular helicase receptors, NSP1 leads to global inhibition of mRNA translation by binding to the 18S ribosomal RNA in the mRNA entry channel, and NSP8 and NSP9 interfere with protein trafficking to the cell membrane; all three mechanisms independently leading to”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The detection of viral RNA in myeloid cells derived from lung or BALF of severe COVID-19 patients still allows several explanations, including phagocytosis of cellular material derived from infected cells, which requires further assessment.”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SARS-CoV-2 enters type II pneumocytes via ACE2 in the respiratory system leading to rapid virus replication as well as concomitantly to a proinflammatory state with elevated levels of cytokines such as IL-1, IL-6, CXCL8, and TNF”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > The next phase—from “cytokine storm” to immunosuppression
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interaction mapping further suggested that NSP13 interacts with TBK1, NSP15 with NRDP1 (an E3 ubiquitin ligase controlling the balance between JAK2-associated cytokine receptor degradation and ectodomain shedding), ORF9b with TOMM70 (an important receptor of the outer mitochondrial membrane), and ORF6 with either KPNA2 or the IFN-induced NUP98-RAE1 nuclear export complex, which are both involved”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Similarly, the pattern recognition receptors (PRRs) involved in recognizing SARS-CoV-2 are not yet directly determined. Based on findings from other coronaviruses, the most likely candidates are Toll-like receptors 3 (TLR3) and TLR7 in the endosome (Mazaleuskaya et al., 2012) or the cytosolic sensors retinoic acid-inducible gene 1 (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) (Sa R”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In in vitro infection models utilizing cell lines, SARS-CoV-2 induced only low type I and II IFNs, consequently inducing only moderate levels of ISGs and a unique proinflammatory cytokine signature including IL1B, IL6, and TNF, as well as many chemokines (CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL16) (Blanco-Melo et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Blanco-Melo et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Accumulation of NF-κB-dependent proinflammatory mediators can provoke an accumulation of pathogenic inflammatory neutrophils and macrophages in the lung”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > The next phase—from “cytokine storm” to immunosuppression
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
In the paper
“RIG-I and MDA5 trigger the downstream adaptor mitochondrial antiviral signaling protein (MAVS) on mitochondria followed by activation of tumor necrosis factor receptor-associated factor 3 (TRAF3), TRAF family member-associated nuclear factor κB (NF-κB) activator binding kinase 1 (TBK1), together with inhibitor of NF-κB kinase-ε (IKK), which leads to phosphorylation of the “master regulators” IRF3”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Loo and Gale, 2011
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“These observations were further extended by illustrating a lack of expression of genes encoding type I IFNs in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and an early but transient wave of ISG expression in blood-derived immune cells, which correlated with an early burst of IFNα, likely of lung origin (Arunachalam et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Arunachalam et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Similar signaling cascades are known downstream of TLR3 and TLR7 (Figure 2C).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Loo and Gale, 2011
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“An early study in patients reported that type I IFNs were either not detected (particularly IFNβ) irrespective of disease severity or at lower levels (IFNα) in plasma mainly derived from patients with severe disease (Hadjadj et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
- Not checked yetcites Hadjadj et al., 2020 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, the virus facilitates the release of coagulation factors, the secretion of inflammatory cytokines, and the formation of leukocyte-platelet aggregates, which might be important mechanisms leading to thromboembolic complications observed in severe COVID-19 (Ackermann et al., 2020; Gupta et al., 2020; Zhang et al., 2020b).”
§ COVID-19 and the human innate immune system > The breach—point of entry for SARS-CoV-2
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Importantly, the type I IFN response can be rather heterogeneous. Depending on the state of the reacting cell (e.g., with respect to its metabolic or general activation state) (Talemi and Höfer, 2018), it is at least in part stochastic (Rand et al., 2012; Wimmers et al., 2018), it varies among different cell types and microenvironments, and it shows interindividual heterogeneity concerning the”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As an immune evasion strategy, SARS-CoV-2 uses a multipronged strategy to antagonize the IFN system with the clinical consequence of an insufficient type I IFN response having been recognized in early COVID-19 studies (Acharya et al., 2020; Blanco-Melo et al., 2020; Sa Ribero et al., 2020).”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Alarming the immune system—recognition, interferon response, and immune evasion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Type I IFN therapy in patients with genetic deficits in the IFN system (Zhang et al., 2020a), but not in those with autoimmune phenocopies of these deficits (Bastard et al., 2020), might be beneficial if provided sufficiently early (Hadjadj et al., 2020; Wang et al., 2020b).”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
What the sources say
- Not matchedcites Zhang et al., 2020a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked yetcites Bastard et al., 2020 source
- Not matchedcites Hadjadj et al., 2020; Wang et al., 2020b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
In the paper
“a scenario emerges with rather differently programmed innate immune cells in mild versus severe disease courses”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Changes in the innate immune cell compartment
What the sources say
- Not checked yetcites Sette and Crotty, 2021 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that immune parameters might be used for disease classification or outcome prediction.”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Immune parameters as biomarkers
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“point toward complement activation as an early innate immune activation mechanism”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > The next phase—from “cytokine storm” to immunosuppression
What the sources say
- Not checked yetcites Shen et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“better summarized as viral sepsis, with the upregulation of proinflammatory mediators being only one part of a derailed innate immune response”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > The next phase—from “cytokine storm” to immunosuppression
What the sources say
- Not checked yetcites Riva et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“four cytokines (IL-6, CXCL8, TNF, and IL-1β) were assessed in serum from 1,484 COVID-19 patients (Del Valle et al., 2020) of which TNF, IL-1β, and IL-6 were elevated in COVID-19 patients, and TNF and IL-6 turned out to be independent predictors of disease severity and fatal outcome.”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Immune parameters as biomarkers
What the sources say
- Not checked yetcites Del Valle et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“suggested that host genetics might contribute to disease susceptibility and severity”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Genetic factors impacting the immune response to SARS-CoV-2
What the sources say
- Not checked yetcites Ovsyannikova et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A specialized form of innate immune adaptation is the induction of immune memory (also termed trained immunity)”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Adaptation of innate immune cells: A role for trained immunity?
What the sources say
- Not checked yetcites Netea et al., 2020a
- Not checked yetcites Giamarellos-Bourboulis et al., 2020b
- Not checked yetcites Moorlag et al., 2020 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Inflammaging is considered a chronic, sterile inflammation characterized by elevated levels of inflammatory mediators in the circulation including IL-6, TNF, CXCL8, CCL2, CRP, and PLA2GD”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Age, inflammaging, and COVID-19
What the sources say
- Not checked yetcites Franceschi et al., 2017 source
- Not checked yetcites Frasca and Blomberg, 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Mild COVID-19 patients were marked by circulating HLA-DR hi CD11c hi inflammatory monocytes with an interferon-stimulated gene signature”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Changes in the innate immune cell compartment
What the sources say
- Not checked yetcites Schulte-Schrepping et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“suggesting the lung as a source for the elevated plasma levels of type I IFNs early on infection”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Changes in the innate immune cell compartment
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“An increase in circulating neutrophils versus a decrease in lymphocytes has been appreciated as a hallmark of severe COVID-19”
§ COVID-19 and the human innate immune system > Cytokine alterations and innate immune cell responses following infection > Changes in the innate immune cell compartment
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These include chronic fatigue syndrome (Salisbury, 2020) and a spectrum of psychiatric disorders ranging from cognitive decline, depression, to even neurodegeneration (Taquet et al., 2021).”
§ COVID-19 and the human innate immune system > Summary and outlook
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Along these lines, therapies targeting the kallikrein-kinin system with icatibant (van de Veerdonk et al., 2020), or the coagulation system with antibodies against C5a and C3a (Mastellos et al., 2020), have been introduced as additional options to ameliorate clinical symptoms and reduce mortality rates.”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
What the sources say
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“suppressed the production of proinflammatory cytokines in lung macrophages, and the recruitment of neutrophils to the lung (Hoang et al., 2021).”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
What the sources say
- Not checked yetcites Hoang et al., 2021 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, molecular prediction of drug responses may guide the way for precision medicine approaches following patient stratification.”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, dexamethasone was shown to be beneficial, particularly in patients with severe disease courses where it reduced 28-day mortality in randomized clinical trials (RECOVERY Collaborative Group et al., 2021; Tomazini et al., 2020; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020).”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
What the sources say
- Not checked yetcites RECOVERY Collaborative Group et al., 2021
- Not checked yetcites Tomazini et al., 2020 source
- Not checked yetcites WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“different combinations of soluble factors were assessed in different studies in context of COVID-19 with only a few choosing comprehensive approaches (Messner et al., 2020; Su et al., 2020).”
§ COVID-19 and the human innate immune system > Factors that influence disease severity > Immune parameters as biomarkers
What the sources say
- Not checked yetcites Messner et al., 2020 source
- Not checked yetcites Su et al., 2020
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“More evidence accumulates suggesting that a yet unknown fraction of patients will suffer from what is described as Long COVID-19, a chronic illness with very heterogeneous symptoms (Marshall, 2020).”
§ COVID-19 and the human innate immune system > Summary and outlook
What the sources say
- Not checked yetcites Marshall, 2020 source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Based on results from phase-III vaccine trials utilizing mRNA vaccines (Anderson et al., 2020; Polack et al., 2020), two vaccines have been approved in the United States, United Kingdom, Israel, and the European Union, and several million individuals have been vaccinated since late 2020.”
§ COVID-19 and the human innate immune system > Therapeutic options targeting immune deviation
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, the vicious cycle of viral sepsis developing in an affected individual already suffering from chronic obstructive pulmonary disease (COPD) might differ from the disease course observed in an obese person and therefore might require other therapies.”
§ COVID-19 and the human innate immune system > Summary and outlook
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Parameters measurable at earlier phases of the disease would be useful to predict the outcome of viral sepsis.”
§ COVID-19 and the human innate immune system > Summary and outlook
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A better understanding of the molecular immune mechanisms, particularly at the transition from a local to a systemic response phase and during viral sepsis, is a prerequisite to introduce novel therapies.”
§ COVID-19 and the human innate immune system > Summary and outlook
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This is similarly true for a potential role of innate immune cells such as NK cells, innate lymphoid cells, mast cells, basophils, or eosinophils, which have not yet been studied in sufficient detail in COVID-19.”
§ COVID-19 and the human innate immune system > Summary and outlook
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Organ involvement, magnitude of clinical symptoms, and length of this phase is highly variable”
§ COVID-19 and the human innate immune system > Summary and outlook
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The authors state this as an assumption.
The majority of humankind does not have an extended cross-reaction to other viruses of the coronavirus family.
“assuming that the majority of humankind does not have an extended cross-reaction to other viruses of the coronavirus family (Braun et al., 2020; Grifoni et al., 2020; Mateus et al., 2020)”
The authors state this as an assumption.
Most steps of the interaction between the virus and the host follow a normal distribution of attributes or parameters required to describe the outcome of the interaction.
“Bearing in mind that most of the steps of the interaction between the virus and the host will follow a normal distribution of attributes or parameters required to describe the outcome of the interaction”
The paper relies on this without support.
The virus counteracts the type I IFN system.
“Because SARS-CoV-2 antagonizes the type I IFN system”
The paper relies on this without support.
COVID-19 is clinically heterogeneous.
“Because COVID-19 presents with such heterogeneity”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Like other pathogenic respiratory RNA viruses (including other coronaviruses, respiratory syncytial virus and enteroviruses)55, SARS-CoV-2 can evade innate immune responses via multiple mechanisms55,56, indicating that innate immunity is likely crucial for host protection54,57.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [56]
Citations
Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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A new coronavirus associated with human respiratory disease in China
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“, 2020), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kim et al., 2020; Wu et al., 2020; Yao et al., 2020; Zhang and Holmes, 2020) is a rather heterogeneous disease.”
BackgroundInfluentialDexamethasone in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2021436 · Cited by 11,477
Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report
Horby, P., Lim, W. S., Emberson, J., Mafham, M., Bell, J., Linsell, L., Staplin, N., Brightling, C., Ustianowski, A., Elmahi, E., et al. (2020) · doi:10.1101/2020.06.22.20137273 · Cited by 11,475 · cited 3×
“…shown to be beneficial, particularly in patients with severe disease courses where it reduced 28-day mortality in randomized clinical trials (RECOVERY Collaborative Group et al., 2021; Tomazini et al., 2020; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020).”
BackgroundRichardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., and the Northwell COVID-19 Research Consortium, Barnaby, D. P., Becker, L. B., Chelico, J. D., et al. (2020) · JAMA · doi:10.1001/jama.2020.6775 · Cited by 9,254
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“…and based on its close relationship with the SARS coronavirus (SARS-CoV) (Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, 2020), it became quickly clear that the surface receptor for SARS-CoV (Li et al., 2003), the angiotensin-converting enzyme 2 (ACE2), was…”
BackgroundFactors associated with COVID-19-related death using OpenSAFELY
Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., Curtis, H. J., Mehrkar, A., Evans, D., Inglesby, P., et al. (2020) · Nature · doi:10.1038/s41586-020-2521-4 · Cited by 6,674
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., et al. (2003) · Nature · doi:10.1038/nature02145 · Cited by 5,923
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2015432 · Cited by 5,613 · cited 1×
“Furthermore, the virus facilitates the release of coagulation factors, the secretion of inflammatory cytokines, and the formation of leukocyte-platelet aggregates, which might be important mechanisms leading to thromboembolic complications observed in severe COVID-19 (Ackermann et al., 2020; Gupta et al., 2020; Zhang…”
BackgroundIncidence of thrombotic complications in critically ill ICU patients with COVID-19
Klok, F. A., Kruip, M. J. H. A., van der Meer, N. J. M., Arbous, M. S., Gommers, D. A. M. P. J., Kant, K. M., Kaptein, F. H. J., van Paassen, J., Stals, M. A. M., Huisman, M. V., et al. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.04.013 · Cited by 5,028 · cited 1×
“These findings go hand in hand with the thrombotic complications and coagulopathy frequently found in severe COVID-19 (Klok et al., 2020), because NET formation can seed immunothrombosis (Veras et al.”
BackgroundDysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., Xie, C., Ma, K., Shang, K., Wang, W., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa248 · Cited by 4,775 · cited 2×
“An increase in circulating neutrophils versus a decrease in lymphocytes has been appreciated as a hallmark of severe COVID-19 (Hadjadj et al., 2020; Mathew et al., 2020; Qin et al., 2020; Schulte-Schrepping et al., 2020).”
BackgroundA SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Gordon, D. E., Jang, G. M., Bouhaddou, M., Xu, J., Obernier, K., White, K. M., O’Meara, M. J., Rezelj, V. V., Guo, J. Z., Swaney, D. L., et al. (2020) · Nature · doi:10.1038/s41586-020-2286-9 · Cited by 4,405 · cited 7×
“…NUP98-RAE1 nuclear export complex, which are both involved in nuclear translocation of proinflammatory transcription factors such as IRF3, IRF7, or STAT1, amechanism targeted by numerous other viruses including influenza, all antagonizing IFN signaling (Gordon et al., 2020; Xia et al., 2020).”
BackgroundInfluentialKorber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E. E., Bhattacharya, T., Foley, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.043 · Cited by 4,281
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
Blanco-Melo, D., Nilsson-Payant, B. E., Liu, W.-C., Uhl, S., Hoagland, D., Møller, R., Jordan, T. X., Oishi, K., Panis, M., Sachs, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.026 · Cited by 4,222
Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.015 · Cited by 3,595 · cited 1×
“…and assuming that the majority of humankind does not have an extended cross-reaction to other viruses of the coronavirus family (Braun et al., 2020; Grifoni et al., 2020; Mateus et al., 2020), the introduction of SARS-CoV-2 into the human population is one of the biggest evolutionary events in the…”
BackgroundFajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · cited 2×
“immune hyperactivation in cytokine storm is the failure of resolution of the inflammation (Fajgenbaum and June, 2020).”
BackgroundExtrapulmonary manifestations of COVID-19
Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., Bikdeli, B., Ahluwalia, N., Ausiello, J. C., Wan, E. Y., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0968-3 · Cited by 3,185 · cited 2×
“Disease courses range from mainly asymptomatic and mild courses to more severe and critical courses in 10%–20% of symptomatic patients who are at considerable risk of fatality with many different organ systems involved in differing combinations and with variable symptoms (Gupta et al., 2020) (Box 1).”
BackgroundCell entry mechanisms of SARS-CoV-2
Shang, J., Wan, Y., Luo, C., Ye, G., Geng, Q., Auerbach, A., & Li, F. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003138117 · Cited by 3,142
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Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients
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Defining trained immunity and its role in health and disease
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Self-citationClinical and immunological assessment of asymptomatic SARS-CoV-2 infections
Long, Q.-X., Tang, X.-J., Shi, Q.-L., Li, Q., Deng, H.-J., Yuan, J., Hu, J.-L., Xu, W., Zhang, Y., Lv, F.-J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0965-6 · Cited by 2,686 · cited 1×
“Asymptomatic SARS-CoV-2 infections have been shown to exhibit lower levels of cytokines (Long et al., 2020).”
BackgroundAutoantibodies against type I IFNs in patients with life-threatening COVID-19
Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H.-H., Zhang, Y., Dorgham, K., Philippot, Q., Rosain, J., Béziat, V., et al. (2020) · Science · doi:10.1126/science.abd4585 · Cited by 2,662
Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19
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“ISG, interferon response gene; Mac, macrophage; mDC, myeloid dendritic cell; NKG2A, NK cell receptor (CD159a) encoded by killer cell lectin lectin-like receptor C1, KLRC1; pDC, plasmacytoid dendritic cell; SPP1, secreted phosphoprotein 1 (coding for osteopontin); TGF-B2, transforming growth factor beta 2; TIM3, T cell…”
BackgroundInfluentialAn inflammatory cytokine signature predicts COVID-19 severity and survival
Del Valle, D. M., Kim-Schulze, S., Huang, H.-H., Beckmann, N. D., Nirenberg, S., Wang, B., Lavin, Y., Swartz, T. H., Madduri, D., Stock, A., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1051-9 · Cited by 2,605
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“In absence of cell-type-specific expression maps of SARSCoV-2 viral entry-associated genes, the Human Cell Atlas (HCA) Lung Biological Network investigated the prevalence of ACE2 and TMPRSS2 in the body by analyzing their expression in single-cell RNA sequencing data (scRNA-seq) from multiple tissues from healthy huma…”
BackgroundInfluentialPathological inflammation in patients with COVID-19: a key role for monocytes and macrophages
Merad, M., & Martin, J. C. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0331-4 · Cited by 2,472 · cited 1×
“…or governance by state authorities have an impact on overall disease burden for society (Han et al., 2020), the host itself seems to be the major factor explaining disease severity, infection rates (Merad and Martin, 2020; Vabret et al., 2020), and long-term medical consequences (Marshall, 2020).”
BackgroundZou, X., Chen, K., Zou, J., Han, P., Hao, J., & Han, Z. (2020) · Frontiers of Medicine · doi:10.1007/s11684-020-0754-0 · Cited by 2,287 · cited 1×
“In the lung, ACE2 and TMPRSS2 expression has been mainly identified in alveolar epithelial type II cells (Qi et al., 2020; Zou et al., 2020).”
BackgroundZiegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., Cao, Y., Yousif, A. S., Bals, J., Hauser, B. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.035 · Cited by 2,284 · cited 1×
“In the lung, ACE2 and TMPRSS2 expression has been mainly identified in alveolar epithelial type II cells (Qi et al., 2020; Zou et al., 2020).”
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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
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The Architecture of SARS-CoV-2 Transcriptome
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“, 2020), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kim et al., 2020; Wu et al., 2020; Yao et al., 2020; Zhang and Holmes, 2020) is a rather heterogeneous disease.”
BackgroundLongitudinal analyses reveal immunological misfiring in severe COVID-19
Lucas, C., Wong, P., Klein, J., Castro, T. B. R., Silva, J., Sundaram, M., Ellingson, M. K., Mao, T., Oh, J. E., Israelow, B., et al. (2020) · Nature · doi:10.1038/s41586-020-2588-y · Cited by 2,074
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Genomewide Association Study of Severe Covid-19 with Respiratory Failure
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Immune Signaling by RIG-I-like Receptors
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BackgroundAdaptive immunity to SARS-CoV-2 and COVID-19
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“discussed in greater detail elsewhere (Sette and Crotty, 2021), NK cells are affected as well (Giamarellos-Bourboulis et al., 2020a; Hadjadj et al., 2020; Kuri-Cervantes et al., 2020; Zheng et al., 2020a).”
BackgroundResultFunctional exhaustion of antiviral lymphocytes in COVID-19 patients
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BackgroundImmunology of COVID-19: Current State of the Science
Vabret, N., Britton, G. J., Gruber, C., Hegde, S., Kim, J., Kuksin, M., Levantovsky, R., Malle, L., Moreira, A., Park, M. D., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.05.002 · Cited by 1,623
COVID-19: immunopathology and its implications for therapy
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“Not surprisingly, trials targeting cytokines such as IL-6, IL-1, IFNg, IL-1R, TNF, CXCL8, GM-CSF, GM-CSF receptor, or IL-37 have been reported, as well as strategies attempting to achieve disruption of chemokine signaling (e.g., via CCR1, CCR2, and CCR5) to prevent overt innate immune cell recruitment into the lung (W…”
BackgroundInfluentialSafety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults
Anderson, E. J., Rouphael, N. G., Widge, A. T., Jackson, L. A., Roberts, P. C., Makhene, M., Chappell, J. D., Denison, M. R., Stevens, L. J., Pruijssers, A. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2028436 · Cited by 1,523 · cited 1×
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BackgroundMiddleton, E. A., He, X., Denorme, F., Campbell, R. A., Ng, D. C., Salvatore, S., Mostyka, M., Baxter-Stoltzfus, A., Borczuk, A., Loda, M. F., et al. (2020) · Blood · doi:10.1182/blood.2020007008 · Cited by 1,515 · cited 1×
“, 2020) as well as increased NET formation ex vivo (Middleton et al., 2020).”
BackgroundProteomic and Metabolomic Characterization of COVID-19 Patient Sera
Shen, B., Yi, X., Sun, Y., Bi, X., Du, J., Zhang, C., Quan, S., Zhang, F., Sun, R., Qian, L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.032 · Cited by 1,514
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“discussed in greater detail elsewhere (Sette and Crotty, 2021), NK cells are affected as well (Giamarellos-Bourboulis et al., 2020a; Hadjadj et al., 2020; Kuri-Cervantes et al., 2020; Zheng et al., 2020a).”
BackgroundInfluentialA single-cell atlas of the peripheral immune response in patients with severe COVID-19
Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martínez-Colón, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0944-y · Cited by 1,493
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“These include chronic fatigue syndrome (Salisbury, 2020) and a spectrum of psychiatric disorders ranging from cognitive decline, depression, to even neurodegeneration (Taquet et al., 2021).”
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“, 2020), resulting in an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress syndrome (ARDS), pulmonary edema, apoptosis of epithelial cells, and finally vascular damage and multi-organ failure (Berlin et al., 2020; Gandhi et al., 2020).”
BackgroundSevere COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment
Schulte-Schrepping, J., Reusch, N., Paclik, D., Baßler, K., Schlickeiser, S., Zhang, B., Krämer, B., Krammer, T., Brumhard, S., Bonaguro, L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.001 · Cited by 1,461
Self-citationSex differences in immune responses that underlie COVID-19 disease outcomes
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The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity
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“Although many mutations decreased infectivity, the virus variant D614G in the spike protein of SARS-CoV-2 increased infectivity (Li et al., 2020).”
BackgroundEfficacy of Tocilizumab in Patients Hospitalized with Covid-19
Stone, J. H., Frigault, M. J., Serling-Boyd, N. J., Fernandes, A. D., Harvey, L., Foulkes, A. S., Horick, N. K., Healy, B. C., Shah, R., Bensaci, A. M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2028836 · Cited by 1,362
Genetic mechanisms of critical illness in COVID-19
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“, 2020), resulting in an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress syndrome (ARDS), pulmonary edema, apoptosis of epithelial cells, and finally vascular damage and multi-organ failure (Berlin et al., 2020; Gandhi et al., 2020).”
BackgroundSARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
Braun, J., Loyal, L., Frentsch, M., Wendisch, D., Georg, P., Kurth, F., Hippenstiel, S., Dingeldey, M., Kruse, B., Fauchere, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2598-9 · Cited by 1,310 · cited 1×
“…perspective and assuming that the majority of humankind does not have an extended cross-reaction to other viruses of the coronavirus family (Braun et al., 2020; Grifoni et al., 2020; Mateus et al., 2020), the introduction of SARS-CoV-2 into the human population is one of the biggest…”
BackgroundTomazini, B. M., Maia, I. S., Cavalcanti, A. B., Berwanger, O., Rosa, R. G., Veiga, V. C., Avezum, A., Lopes, R. D., Bueno, F. R., Silva, M. V. A. O., et al. (2020) · JAMA · doi:10.1001/jama.2020.17021 · Cited by 1,241 · cited 1×
“…shown to be beneficial, particularly in patients with severe disease courses where it reduced 28-day mortality in randomized clinical trials (RECOVERY Collaborative Group et al., 2021; Tomazini et al., 2020; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020).”
BackgroundArts, R. J. W., Moorlag, S. J. C. F. M., Novakovic, B., Li, Y., Wang, S.-Y., Oosting, M., Kumar, V., Xavier, R. J., Wijmenga, C., Joosten, L. A. B., et al. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2017.12.010 · Cited by 1,217 · cited 1×
“In principle, exposure of innate immune cells and their precursors to either BCG or b-glucan leads to their reprogramming, inducing heterologous protection against other pathogens including viruses (Arts et al., 2018).”
BackgroundSystems biological assessment of immunity to mild versus severe COVID-19 infection in humans
Arunachalam, P. S., Wimmers, F., Mok, C. K. P., Perera, R. A. P. M., Scott, M., Hagan, T., Sigal, N., Feng, Y., Bristow, L., Tak-Yin Tsang, O., et al. (2020) · Science · doi:10.1126/science.abc6261 · Cited by 1,186 · cited 7×
“…Silvin et al., 2020), however, joining forces to address some of the suggested early predictors and validate them in larger multicenter trials (Arunachalam et al., 2020; Su et al., 2020) utilizing high-content, high-throughput, high-resolution technologies is the next step to study COVID19…”
BackgroundInfluentialSelective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans
Mateus, J., Grifoni, A., Tarke, A., Sidney, J., Ramirez, S. I., Dan, J. M., Burger, Z. C., Rawlings, S. A., Smith, D. M., Phillips, E., et al. (2020) · Science · doi:10.1126/science.abd3871 · Cited by 1,120 · cited 2×
“Looking at the current pandemic entirely from a biological perspective and assuming that the majority of humankind does not have an extended cross-reaction to other viruses of the coronavirus family (Braun et al., 2020; Grifoni et al., 2020; Mateus et al., 2020), the introduction of SARS-CoV-2 into the human populatio…”
BackgroundCytokine Storm in COVID-19: The Current Evidence and Treatment Strategies
Tang, Y., Liu, J., Zhang, D., Xu, Z., Ji, J., & Wen, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01708 · Cited by 1,094
Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals
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“In early studies on patients during convalescence, an increased frequency of NK cells was reported (Ni et al., 2020; Rodriguez et al., 2020).”
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“Furthermore, there has been no evidence for the role of innate immune cells in SARS-CoV-2 gaining access to the retina (de Figueiredo et al., 2020) or the brain (Song et al., 2021), albeit the virus has been found in both organs.”
BackgroundAge-dependent dysregulation of innate immunity
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“In this setting, with defective functionality in the myeloid compartment along an increase in proinflammatory monocytes and higher baseline levels of many proinflammatory mediators such as IL6 (Shaw et al., 2013), it can be hypothesized that the initiated innate immune response during COVID-19 exacerbates the already…”
BackgroundInfluentialMolecular Architecture of the SARS-CoV-2 Virus
Yao, H., Song, Y., Chen, Y., Wu, N., Xu, J., Sun, C., Zhang, J., Weng, T., Zhang, Z., Wu, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.018 · Cited by 1,060 · cited 2×
“, 2020), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kim et al., 2020; Wu et al., 2020; Yao et al., 2020; Zhang and Holmes, 2020) is a rather heterogeneous disease.”
BackgroundLiu, Y., Du, X., Chen, J., Jin, Y., Peng, L. H., Wang, H., Luo, M., Chen, L., & Zhao, Y. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.04.002 · Cited by 1,057 · cited 1×
“, 2020), and an elevated neutrophil/lymphocyte ratio has been introduced as a biomarker of disease severity (Kuri-Cervantes et al., 2020; Lagunas-Rangel, 2020; Liu et al., 2020; Qin et al., 2020).”
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“The local mucosal immune response to SARS-CoV-2 infection has been characterized by cellular and transcriptional changes in the upper respiratory tract (Chua et al., 2020) as well as in BALF assessing the lower, more distal parts of the lung (Liao et al.”
BackgroundInfluentialSyrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development
Imai, M., Iwatsuki‐Horimoto, K., Hatta, M., Loeber, S. J., Halfmann, P., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009799117 · Cited by 994
Activation and evasion of type I interferon responses by SARS-CoV-2
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“Functional testing further supported the counteracting activity of ORF3b, ORF6, NSP1, or NSP13 on type I IFN activation, of which particularly ORF6 suppressed STAT1 and STAT2 phosphorylation and STAT1 nuclear translocation, (Konno et al., 2020; Lei et al., 2020; Xia et al., 2020).”
BackgroundEvasion of Type I Interferon by SARS-CoV-2
Xia, H., Cao, Z., Xie, X., Zhang, X., Chen, J. Y.-C., Wang, H., Menachery, V. D., Rajsbaum, R., & Shi, P.-Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108234 · Cited by 957 · cited 3×
“Interaction mapping further suggested that NSP13 interacts with TBK1, NSP15 with NRDP1 (an E3 ubiquitin ligase controlling the balance between JAK2-associated cytokine receptor degradation and ectodomain shedding), ORF9b with TOMM70 (an important receptor of the outer mitochondrial membrane), and ORF6 with either KPNA…”
BackgroundSARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology
Veras, F. P., Pontelli, M. C., Silva, C. M. S., Toller-Kawahisa, J. E., de Lima, M., Nascimento, D. C., Schneider, A. H., Caetité, D. B., Tavares, L., Paiva, I. M., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201129 · Cited by 949
A dynamic COVID-19 immune signature includes associations with poor prognosis
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The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19
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A Genomic Perspective on the Origin and Emergence of SARS-CoV-2
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“…they identified 13, mainly loss-of-function mutations, associated with severe COVID-19 disease course in the TLR3, IRF7, and IRF9 pathways (Zhang et al., 2020a) (Figure 5). pDCs from IRF7-deficient patients produced no type I IFN when infected with SARS-CoV-2, and fibroblasts from…”
BackgroundInfluentialElevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19
Silvin, A., Chapuis, N., Dunsmore, G., Goubet, A.-G., Dubuisson, A., Derosa, L., Almire, C., Hénon, C., Kosmider, O., Droin, N., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.002 · Cited by 834
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TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib
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“…(Xiong et al., 2020) but also in the circulation (IL-1, IFNg, IL-17, TNF, IP-10, MCP-1, G-CSF, GM-CSF, IL-1RA, CCL2, CCL3, CCL5, CCL8, CXCL2, CXCL8, CXCL9, and CXCL16) (Blanco-Melo et al., 2020; Hadjadj et al., 2020; Huang et al., 2020; Wang et al., 2020a; Wu and Yang, 2020; Yang et al., 2020b).”
BackgroundInfluentialPresence of Genetic Variants Among Young Men With Severe COVID-19
van der Made, C. I., Simons, A., Schuurs-Hoeijmakers, J., van den Heuvel, G., Mantere, T., Kersten, S., van Deuren, R. C., Steehouwer, M., van Reijmersdal, S. V., Jaeger, M., et al. (2020) · JAMA · doi:10.1001/jama.2020.13719 · Cited by 789
Emerging Pandemic Diseases: How We Got to COVID-19
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“Similar to SARS-CoV (Matsuyama et al., 2010), SARS-CoV-2 employs the cellular serine protease TMPRSS2 for S protein priming.”
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Is a “Cytokine Storm” Relevant to COVID-19?
Sinha, P., Matthay, M. A., & Calfee, C. S. (2020) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2020.3313 · Cited by 724 · cited 2×
“Critical voices have since raised concerns whether cytokine storm or CRS reflects the immune response in COVID-19 patients correctly (Sinha et al., 2020), noting that the observed elevated IL-6 levels are considerably lower than e.g., in septic shock or CRS due to other causes (Kox et al., 2020;…”
BackgroundComprehensive mapping of immune perturbations associated with severe COVID-19
Kuri-Cervantes, L., Pampena, M. B., Meng, W., Rosenfeld, A. M., Ittner, C. A. G., Weisman, A. R., Agyekum, R. S., Mathew, D., Baxter, A. E., Vella, L. A., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd7114 · Cited by 723 · cited 3×
“discussed in greater detail elsewhere (Sette and Crotty, 2021), NK cells are affected as well (Giamarellos-Bourboulis et al., 2020a; Hadjadj et al., 2020; Kuri-Cervantes et al., 2020; Zheng et al., 2020a).”
BackgroundCytokine storms: understanding COVID-19
Mangalmurti, N., & Hunter, C. A. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.017 · Cited by 698 · cited 1×
“On the other hand, the definition of cytokine storm has expanded to conditions beyond sepsis and, irrespective of absolute cytokine concentrations, to include all inflammatory conditions with elevated circulating cytokines that result in systemic inflammation as well as secondary organ dysfunction (Fajgenbaum and June…”
BackgroundSARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
Zhang, S., Liu, Y., Wang, X., Li, H., Li, H., Wang, Y., Liu, M., Zhao, X., Xie, Y., Yang, Y., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00954-7 · Cited by 673 · cited 1×
“From experiments with SARS-CoV, it has been postulated that particularly altered innate immune responses in aged animals contribute to severe disease courses (Smits et al., 2010; Zhao et al., 2011).”
MethodThe major genetic risk factor for severe COVID-19 is inherited from Neanderthals
Zeberg, H., & Pääbo, S. (2020) · Nature · doi:10.1038/s41586-020-2818-3 · Cited by 636 · cited 1×
“Coronavirus disease 2019 (COVID-19) (Berlin et al., 2020; Gandhi et al., 2020), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kim et al., 2020; Wu et al., 2020; Yao et al., 2020; Zhang and Holmes, 2020) is a rather heterogeneous disease.”
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“…lymphopenia has been identified as a hallmark of severe COVID-19 (Guan et al., 2020; Huang et al., 2020), and an elevated neutrophil/lymphocyte ratio has been introduced as a biomarker of disease severity (Kuri-Cervantes et al., 2020; Lagunas-Rangel, 2020; Liu et al., 2020; Qin et al., 2020).”
BackgroundMulti-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19
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BackgroundMethodInfluentialStructural Basis of Preexisting Immunity to the 2009 H1N1 Pandemic Influenza Virus
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BackgroundEvolution and epidemic spread of SARS-CoV-2 in Brazil
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Decoding type I and III interferon signalling during viral infection
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“The ability to fine-tune an IFN response is critical because both its overactivation and underactivation are deleterious to the host (Mesev et al., 2019).”
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“Handling of the infection in the upper respiratory tract (the major entry point of SARS-CoV-2), managing viral clearance, and consequent resolution of the active immune response, is a key aspect for prevention of viral dissemination into the lung and pulmonary injury (Newton et al., 2016).”
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Dysregulation of type I interferon responses in COVID-19
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BackgroundInterplay between SARS-CoV-2 and the type I interferon response
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BCG vaccine protection from severe coronavirus disease 2019 (COVID-19)
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“…studies on the impact of BCG vaccination in childhood resulted in contradictory results concerning a beneficial role for fighting SARS-CoV-2 infection (de Chaisemartin and de Chaisemartin, 2020; Escobar et al., 2020; Hamiel et al., 2020; Kinoshita and Tanaka, 2020; Lindestam Arlehamn et al., 2020).”
ResultKonno, Y., Kimura, I., Uriu, K., Fukushi, M., Irie, T., Koyanagi, Y., Sauter, D., Gifford, R. J., Nakagawa, S., & Sato, K. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108185 · Cited by 433
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“…balance at the early steps of a SARS-CoV-2 infection for each patient individually might be critical to better stratify patients and to allow for patient-tailored treatment options thereby preventing the development of immunopathology as the basis for severe disease courses (Lee and Shin, 2020).”
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Interferon-α2b Treatment for COVID-19
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Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
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Aging, obesity, and inflammatory age-related diseases
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Self-citationInflammaging decreases adaptive and innate immune responses in mice and humans
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BackgroundThe coronavirus is mutating — does it matter?
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“These processes are in full swing and accelerate as more individuals become infected (Callaway, 2020; Cyranoski, 2020; Korber et al., 2020).”
BackgroundPlasma Proteomics Identify Biomarkers and Pathogenesis of COVID-19
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BackgroundResultInfluentialCoronavirus Disease 2019 Treatment: A Review of Early and Emerging Options
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“Further, because basophils have been implicated in potentiating the humoral immune response (Denzel et al., 2008), thismight constitute another avenue of innate-adaptive crosstalk in COVID-19.”
BackgroundSingle-cell chromatin modification profiling reveals increased epigenetic variations with aging
Cheung, P., Vallania, F., Warsinske, H. C., Donato, M., Schaffert, S., Chang, S. E., Dvorak, M., Dekker, C. L., Davis, M. M., Utz, P. J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.079 · Cited by 323 · cited 1×
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“Systemically, the aged innate immune system shares another hallmark of severe COVID-19, namely increased myelopoiesis with elevated numbers of myeloid cells including neutrophils and monocytes in circulation and inflammatory macrophages in the tissues (Ho et al., 2019).”
BackgroundSevere immunosuppression and not a cytokine storm characterizes COVID-19 infections
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The lasting misery of coronavirus long-haulers
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“More evidence accumulates suggesting that a yet unknown fraction of patients will suffer from what is described as Long COVID-19, a chronic illness with very heterogeneous symptoms (Marshall, 2020).”
BackgroundBaricitinib restrains the immune dysregulation in patients with severe COVID-19
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Self-citationDeciphering the COVID‐19 cytokine storm: Systematic review and meta‐analysis
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“For a particularly strong manifestation of all these changes, the term inflammaging was coined (Boren and Gershwin, 2004; Franceschi et al., 2017).”
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“Furthermore, knockout of CCR1 in mice supports that this receptor protects from excessive inflammatory response (Gerard et al., 1997) and decreases susceptibility to viruses and fungi (Blease et al., 2000).”
BackgroundSARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults
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“…studies on the impact of BCG vaccination in childhood resulted in contradictory results concerning a beneficial role for fighting SARS-CoV-2 infection (de Chaisemartin and de Chaisemartin, 2020; Escobar et al., 2020; Hamiel et al., 2020; Kinoshita and Tanaka, 2020; Lindestam Arlehamn et al., 2020).”
ResultSystems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19
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Profile of a killer: the complex biology powering the coronavirus pandemic
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“These processes are in full swing and accelerate as more individuals become infected (Callaway, 2020; Cyranoski, 2020; Korber et al., 2020).”
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“…immune adaptation is the induction of immune memory (also termed trained immunity) (Netea et al., 2020a), best characterized for BCG vaccination (GiamarellosBourboulis et al., 2020b;Moorlag et al., 2020) and b-glucan stimulation of monocytes (Dos Santos et al., 2019; Kleinnijenhuis et al., 2012).”
BackgroundViral load of SARS-CoV-2 across patients and compared to other respiratory viruses
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BackgroundSustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection
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Trained Innate Immunity, Epigenetics, and Covid-19
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BackgroundLifeTime and improving European healthcare through cell-based interceptive medicine
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Self-citationAging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
Molony, R. D., Nguyen, J. T., Kong, Y., Montgomery, R. R., Shaw, A. C., & Iwasaki, A. (2017) · Science Signaling · doi:10.1126/scisignal.aan2392 · Cited by 154 · cited 1×
“This is accompanied with reduced type I IFN production combined with perturbed inflammatory cytokine responses to viral infections (Canaday et al., 2010; Molony et al., 2017).”
BackgroundWimmers, F., Subedi, N., van Buuringen, N., Heister, D., Vivié, J., Beeren-Reinieren, I., Woestenenk, R., Dolstra, H., Piruska, A., Jacobs, J. F. M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05784-3 · Cited by 150 · cited 1×
“, with respect to its metabolic or general activation state) (Talemi and Höfer, 2018), it is at least in part stochastic (Rand et al., 2012; Wimmers et al., 2018), it varies among different cell types andmicroenvironments, and it shows interindividual heterogeneity concerning the amplitude and kinetics (Patil et al.”
BackgroundMulti-layered stochasticity and paracrine signal propagation shape the type-I interferon response
Rand, U., Rinas, M., Schwerk, J., Nöhren, G., Linnes, M., Kröger, A., Flossdorf, M., Kály‐Kullai, K., Hauser, H., Höfer, T., et al. (2012) · Molecular Systems Biology · doi:10.1038/msb.2012.17 · Cited by 147
Severe COVID-19 and aging: are monocytes the key?
Pence, B. D. (2020) · GeroScience · doi:10.1007/s11357-020-00213-0 · Cited by 137 · cited 1×
“The effect of the age-associated changes seen in both the innate and the adaptive arm of the immune system have been investigated in several animal models in the context of coronavirus infection (Channappanavar and Perlman, 2020; Pence, 2020).”
BackgroundCOVID-19: In the Eye of the Cytokine Storm
de la Rica, R., Borges-Sa, M., & González‐Freire, M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.558898 · Cited by 134 · cited 1×
“…that COVID-19, particularly severe disease courses, might be associated with a maladapted induction of an immune response to the infection leading to what has been previously termed a ‘‘cytokine storm’’ or cytokine release syndrome (CRS) (Mulchandani et al., 2021; de la Rica et al., 2020).”
BackgroundAshary, N., Bhide, A., Chakraborty, P., Colaco, S., Mishra, A., Chhabria, K., Jolly, M. K., & Modi, D. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00783 · Cited by 121 · cited 2×
“Similarly, the human placenta is highly susceptible to SARS-CoV-2 infection, but only non-immune cells including syncytiotrophoblasts in the first trimester and extravillous trophoblasts in the second trimester express ACE2 and TMPRSS2 and have been identified as cellular targets for the virus (Ashary et al., 2020).”
BackgroundAnakinra treatment in critically ill COVID-19 patients: a prospective cohort study
the RCI-COVID-19 Study Group, Kooistra, E. J., Waalders, N. J. B., Grondman, I., Janssen, N. A. F., de Nooijer, A. H., Netea, M. G., van de Veerdonk, F. L., Ewalds, E., van der Hoeven, J. G., et al. (2020) · Critical Care · doi:10.1186/s13054-020-03364-w · Cited by 119 · cited 1×
“Thismight be similarly true for targeting IL-1 with anakinra for which several smaller studies were reporting beneficial effects (Iglesias-Julián et al., 2020; Kooistra et al., 2020), yet results from larger randomized trials are still missing.”
BackgroundPlatelet–Neutrophil Crosstalk in Atherothrombosis
Pircher, J., Engelmann, B., Maßberg, S., & Schulz, C. (2019) · Thrombosis and Haemostasis · doi:10.1055/s-0039-1692983 · Cited by 118
Airway Remodeling Is Absent in CCR1−/− Mice During Chronic Fungal Allergic Airway Disease
Blease, K., Mehrad, B., Standiford, T. J., Lukacs, N. W., Kunkel, S. L., Chensue, S. W., Lu, B., Gerard, C. J., & Hogaboam, C. M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.3.1564 · Cited by 116
Amor, S., Blanco, L. F., & Baker, D. (2020) · Clinical & Experimental Immunology · doi:10.1111/cei.13523 · Cited by 114 · cited 2×
“In such an evolutionary experiment, the innate immune system must be assigned a very special role in the defense against SARS-CoV-2 (Amor et al., 2020; Mantovani and Netea, 2020; Vabret et al., 2020).”
BackgroundThe dynamic changes in cytokine responses in COVID-19: a snapshot of the current state of knowledge
Buszko, M., Park, J., Verthelyi, D. I., Sen, R., Young, H. A., & Rosenberg, A. S. (2020) · Nature Immunology · doi:10.1038/s41590-020-0779-1 · Cited by 104 · cited 1×
“This is critical when considering the development of stratified therapies (Buszko et al., 2020).”
BackgroundAge-severity matched cytokine profiling reveals specific signatures in Covid-19 patients
Angioni, R., Sánchez‐Rodríguez, R., Munari, F., Bertoldi, N., Arcidiacono, D., Cavinato, S., Marturano, D., Zaramella, A., Realdon, S., Cattelan, A. M., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03151-z · Cited by 101 · cited 1×
“A recent study illustrated that age has an impact on the inflammatory mediators present during COVID-19 (Angioni et al., 2020).”
BackgroundMoorlag, S. J. C. F. M., van Deuren, R. C., van Werkhoven, C. H., Jaeger, M., Debisarun, P., Taks, E., Mourits, V. P., Koeken, V. A. C. M., de Bree, L. C. J., ten Doesschate, T., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100073 · Cited by 96 · cited 1×
“, 2020a), best characterized for BCG vaccination (GiamarellosBourboulis et al., 2020b;Moorlag et al., 2020) and b-glucan stimulation of monocytes (Dos Santos et al.”
BackgroundChannappanavar, R., & Perlman, S. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci144115 · Cited by 94 · cited 1×
“The effect of the age-associated changes seen in both the innate and the adaptive arm of the immune system have been investigated in several animal models in the context of coronavirus infection (Channappanavar and Perlman, 2020; Pence, 2020).”
BackgroundMazaleuskaya, L., Veltrop, R., Ikpeze, N., Martin-Garcia, J., & Navas-Martin, S. (2012) · Viruses · doi:10.3390/v4050901 · Cited by 89
Influenza-Induced Production of Interferon-Alpha is Defective in Geriatric Individuals
Canaday, D. H., Amponsah, N. A., Jones, L., Tisch, D. J., Hornick, T. R., & Ramachandra, L. (2010) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9374-9 · Cited by 89 · cited 1×
“This is accompanied with reduced type I IFN production combined with perturbed inflammatory cytokine responses to viral infections (Canaday et al., 2010; Molony et al., 2017).”
BackgroundPatil, S., Fribourg, M., Ge, Y., Batish, M., Tyagi, S., Hayot, F., & Sealfon, S. C. (2015) · Science Signaling · doi:10.1126/scisignal.2005728 · Cited by 80
Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19
van de Veerdonk, F. L., Kouijzer, I. J. E., de Nooijer, A. H., van der Hoeven, H. G., Maas, C., Netea, M. G., & Brüggemann, R. J. M. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.17708 · Cited by 65 · cited 1×
“Along these lines, therapies targeting the kallikrein-kinin system with icatibant (van de Veerdonk et al., 2020), or the coagulation system with antibodies against C5a and C3a (Mastellos et al., 2020), have been introduced as additional options to ameliorate clinical symptomsand reducemortality…”
BackgroundIglesias-Julián, E., López-Veloso, M., de-la-Torre-Ferrera, N., Barraza-Vengoechea, J. C., Delgado-López, P. D., Colazo-Burlato, M., Ubeira-Iglesias, M., Montero-Baladía, M., Lorenzo-Martín, A., Minguito-de-la-Iglesia, J., et al. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2020.102537 · Cited by 62 · cited 2×
“Thismight be similarly true for targeting IL-1 with anakinra for which several smaller studies were reporting beneficial effects (Iglesias-Julián et al., 2020; Kooistra et al., 2020), yet results from larger randomized trials are still missing.”
BackgroundLack of evidence for BCG vaccine protection from severe COVID-19
Arlehamn, C. S. L., Sette, A., & Peters, B. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016733117 · Cited by 51 · cited 1×
“…studies on the impact of BCG vaccination in childhood resulted in contradictory results concerning a beneficial role for fighting SARS-CoV-2 infection (de Chaisemartin and de Chaisemartin, 2020; Escobar et al., 2020; Hamiel et al., 2020; Kinoshita and Tanaka, 2020; Lindestam Arlehamn et al., 2020).”
ResultTocilizumab for Covid-19 — The Ongoing Search for Effective Therapies
Huang, E., & Jordan, S. C. (2020) · New England Journal of Medicine · doi:10.1056/nejme2032071 · Cited by 48 · cited 2×
“For example, inconsistent results have been reported from large clinical trials when trying to inhibit IL-6 associated with hyperinflammation (Huang and Jordan, 2020).”
ResultCOVID-19: more than a cytokine storm
Riva, G., Nasillo, V., Tagliafico, E., Trenti, T., Comoli, P., & Luppi, M. (2020) · Critical Care · doi:10.1186/s13054-020-03267-w · Cited by 46 · cited 2×
“Three major concepts emerge concerning therapeutic and preventive options in COVID-19: (1) targeting the virus and its cellular life cycle by antiviral drugs, (2) developing vaccines that can either prevent or mitigate disease symptoms after infection, and (3) targeting the deviation of the immune response to avoid or…”
BackgroundImpact of Routine Infant BCG Vaccination on COVID-19
Kinoshita, M., & Tanaka, M. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.08.013 · Cited by 42
“Trained immunity” from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes
Singh, S., Maurya, R. P., & Singh, R. K. (2020) · PLOS Pathogens · doi:10.1371/journal.ppat.1008969 · Cited by 41 · cited 1×
“…recent epidemiological observations from the first wave of the pandemic indicate that the prevalence of individuals with positive tuberculin sensitivity tests—either due to exposure to Mycobacterium spp. or BCG vaccination—inversely correlates with the incidence of COVID-19 (Singh et al., 2020).”
BackgroundTargeting Host Cell Proteases to Prevent SARS-CoV-2 Invasion
Kaur, U., Chakrabarti, S. S., Ojha, B., Pathak, B. K., Singh, A. K., Saso, L., & Chakrabarti, S. (2020) · Current Drug Targets · doi:10.2174/1389450121666200924113243 · Cited by 36
SARS-CoV-2 Targeting the Retina: Host-virus Interaction and Possible Mechanisms of Viral Tropism
de Figueiredo, C. S., Raony, Í., & Giestal-de-Araujo, E. (2020) · Ocular Immunology and Inflammation · doi:10.1080/09273948.2020.1799037 · Cited by 32 · cited 1×
“Furthermore, there has been no evidence for the role of innate immune cells in SARS-CoV-2 gaining access to the retina (de Figueiredo et al., 2020) or the brain (Song et al., 2021), albeit the virus has been found in both organs.”
BackgroundIslam, M. M., Poly, T. N., Walther, B. A., Yang, H., Wang, C., Hsieh, W.-S., Atique, S., Salmani, H., Alsinglawi, B. S., Lin, M. C., et al. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.573468 · Cited by 31 · cited 1×
“Yet, based on clinical observations, there is no evidence for vertical transmission of the virus from infected mothers to the fetus (Islam et al., 2020) arguing for a protective role of the maternal immune response, which requires further exploitation.”
BackgroundAntiviral interferon response at single‐cell resolution
Talemi, S. R., & Höfer, T. (2018) · Immunological Reviews · doi:10.1111/imr.12699 · Cited by 30 · cited 1×
“, with respect to its metabolic or general activation state) (Talemi and Höfer, 2018), it is at least in part stochastic (Rand et al.”
BackgroundHelen Salisbury: When will we be well again?
Salisbury, H. (2020) · BMJ · doi:10.1136/bmj.m2490 · Cited by 20 · cited 2×
“These include chronic fatigue syndrome (Salisbury, 2020) and a spectrum of psychiatric disorders ranging from cognitive decline, depression, to even neurodegeneration (Taquet et al., 2021).”
BackgroundCOVID-19: What type of cytokine storm are we dealing with?
Monneret, G., Benlyamani, I., Gossez, M., Bermejo‐Martin, J. F., Martín‐Fernandez, M., Sesques, P., Wallet, F., & Venet, F. (2021) · Journal of Medical Virology · doi:10.1002/jmv.26317 · Cited by 18
Immune Response Resetting as a Novel Strategy to Overcome SARS-CoV-2–Induced Cytokine Storm
Nowill, A. E., & de Campos-Lima, P. O. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000892 · Cited by 17 · cited 1×
“In late 2020, 21 newly initiated trials assessing protective effects of BCG vaccination against COVID-19 and 3 trials assessing VPM1002, a further development of the old BCG vaccine, were registered at https://ClinicalTrials.gov (accessed 2021/01/19) (Nowill and de Campos-Lima, 2020).”
BackgroundTargeting host cell proteases to prevent SARS-CoV-2 invasion
Kaur, U. (2021) · Current Drug Targets · doi:10.2174/18735592mtewnmtk90 · Cited by 14
Flagged first, then by citations
Research works printed but not linked: 2
- de Chaisemartin, 2020, BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden, Clin. Infect. Dis.
- Muus, 2021, Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells, Nat Med.
Cited by
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Immunological mechanisms of vaccine-induced protection against COVID-19 in humans
Sadarangani, M., Marchant, A., & Kollmann, T. R. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00578-z · Cited by 560
Innate immunity: the first line of defense against SARS-CoV-2
Diamond, M., & Kanneganti, T. (2022) · Nature Immunology · doi:10.1038/s41590-021-01091-0 · Cited by 639
Local and systemic responses to SARS-CoV-2 infection in children and adults
Yoshida, M., Worlock, K. B., Huang, N., Lindeboom, R. G. H., Butler, C. R., Kumasaka, N., Dominguez Conde, C., Mamanova, L., Bolt, L., Richardson, L., et al. (2022) · Nature · doi:10.1038/s41586-021-04345-x · Cited by 365
Carbon Dots in Bioimaging, Biosensing and Therapeutics: A Comprehensive Review
Wang, B., Cai, H., Waterhouse, G. I. N., Qu, X., Yang, B. J., & Lu, S. (2022) · Small Science · doi:10.1002/smsc.202200012 · Cited by 424
Human genetic and immunological determinants of critical COVID-19 pneumonia
Zhang, Q., Bastard, P., Effort, C. H. G., Karbuz, A., Gervais, A., Tayoun, A. N. A., Aiuti, A., Bélot, A., Bolze, A., Gaudet, A., et al. (2022) · Nature · doi:10.1038/s41586-022-04447-0 · Cited by 377
Metadata
- Authors
- Schultze, J. L., & Aschenbrenner, A. C.
- Affiliations
- University of Bonn (DE)
- Corresponding author
- Schultze, Joachim L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 184
- Issue
- 7
- Pages
- 1671-1692
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7885626
- OpenAlex
- W3131820551
- Cited by
- 714
- References
- 202
- Citations by year
- 2026: 30 · 2025: 57 · 2024: 96 · 2023: 174 · 2022: 235 · 2021: 122
- FWCI
- 18.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- COVID-19 pandemic, SARS-CoV-2, innate immunity, disease heterogeneity, soluble immune mediators, pathophysiology, diagnostic biomarkers, treatment options, host-virus interaction
- MeSH terms
- Host Microbial Interactions, COVID-19, SARS-CoV-2, Humans, Immunity, Innate, Severity of Illness Index
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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