The DOI matches its Crossref record; 194 of the 194 references it cites were found in a registry or an index; 1 of the 147 sources its claims cite were checked for support.
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
AI snapshot
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.
Integrity signals
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Verification
Claims the paper makes
96 Not checked yet · 19 Own interpretation · 3 No basis given · 1 Not supported · accuracy not yet measured
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In 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
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- It may state two separate claims as one. 53
- Probably not a substantial claim. 9
- The quote only partly states this claim. 4
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
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
- Disputedcites Tomazini et al., 2020 sourceExperimental — accuracy not yet measured
The Secondary Outcomes and Adverse Events section reports no significant difference in 28-day all-cause mortality between dexamethasone and standard care (56.3% vs 61.5%; P = .85). The Discussion explicitly contrasts this result with the RECOVERY trial. CoDEX found more ventilator-free days, but did not show that dexamethasone reduced 28-day mortality in its patients with moderate or severe COVID-19 ARDS. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
- Not checked yetcites WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a 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
“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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelationaln = 1,484- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a 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
“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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884
Clinical characteristics of coronavirus disease 2019 in China
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., Liu, L., Shan, H., Lei, C.-L., Hui, D. S. C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2002032 · Cited by 30,246
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2034577 · Cited by 14,592
A new coronavirus associated with human respiratory disease in China
Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., Hu, Y., Tao, Z.-W., Tian, J.-H., Pei, Y.-Y., et al. (2020) · Nature · doi:10.1038/s41586-020-2008-3 · Cited by 11,688 · cited 4×
“, 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
Gorbalenya, A. E., Baker, S. C., Baric, R. S., de Groot, R. J., Drosten, C., Gulyaeva, A. A., Haagmans, B. L., Lauber, C., Leontovich, A. M., Neuman, B. W., et al. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0695-z · Cited by 8,745 · cited 2×
“…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
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
Sorted by citations
Items 201–300 of 612
Hada, M., Mosholder, A., Leishear, K., & Perez-Vilar, S. (2022) · Neurological Sciences · doi:10.1007/s10072-021-05846-3 · Cited by 17
“An effective immune response against SARS-CoV-2 infection requires both arms of the immune system, innate and adaptive [26, 27].”
BackgroundPorter, N. S., & Jason, L. A. (2022) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s379653 · Cited by 24
“Individuals with COVID-19 display a pattern of immunologic association reflective of a more global pattern of activation, characterized by increased interrelationship among proteins with a differential grouping of proteins.(61,62) Taken together, this research suggests that a pro-inflammatory cytokine profile occurs w…”
BackgroundXiong, Y., Li, Y., Qian, W.-W., & Zhang, Q. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1380697 · Cited by 17
“Signaling through these receptors in innate immune cells in response to pathogens, PAMP or DAMP, triggers the production of in fl ammatory cytokines and chemokines while inducing cell death to clear the infected cells (77, 78).”
Backgrounddos Santos, O. V., Langley, A. C. D. C. P., de Lima, A. J. M., Moraes, V. S. V., Soares, S. D., & Teixeira-Costa, B. E. (2022) · Journal of Functional Foods · doi:10.1016/j.jff.2022.105123 · Cited by 16
Biomarkers in immunology: Their impact on immune function and response
Kaushik, D., Xu, B., & Kumar, M. (2025) · Advances in Biomarker Sciences and Technology · doi:10.1016/j.abst.2025.03.001 · Cited by 14
Alipanah, N., Hurst‐Hopf, J., Delucchi, K., Swigart, L. B., Willmore, A., Lacombe, B., Dewar, R. L., Lane, H. C., Lallemand, P., Liu, K. D., et al. (2024) · Critical Care · doi:10.1186/s13054-024-04819-0 · Cited by 16
“Studies on the host immunologic response to SARS-CoV-2 have found associations between circulating levels of interleukin-(IL-) 6, tumor necrosis factor (TNF), interferon-(IFN-) α, IL-10 and other cytokines with outcomes in those with moderate to severe disease [4].”
BackgroundSayed, D. F., Afifi, A. H., Temraz, A., & Ahmed, A. (2023) · Arabian Journal of Chemistry · doi:10.1016/j.arabjc.2023.104753 · Cited by 16
Globenko, A. A., Kuzin, G. V., Rydlovskaya, A. V., Ei, I., Ветрова, Е. Н., Pritchina, T. N., Baranova, A. V., & Nebolsin, V. E. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1087850 · Cited by 17
Maleknia, S., Tavassolifar, M. J., Mottaghitalab, F., Zali, M., & Meyfour, A. (2022) · Molecular Medicine · doi:10.1186/s10020-022-00513-5 · Cited by 16
RAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity
Angioni, R., Bonfanti, M., Caporale, N., Sánchez‐Rodríguez, R., Munari, F., Savino, A., Pasqualato, S., Buratto, D., Pagani, I., Bertoldi, N., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101266 · Cited by 24
“We expressed and purified from mammalian cells (Figure S6) the first moiety of RAGE (construct 1–231, which results in soluble RAGE 23–231 upon secretion) and two constructs of S: its whole extracellular domain (ECD) and RBD. 42 We used microscale thermophoresis and measured a K D of (cid”
BackgroundMethodAuld, S. C., Sheshadri, A., Alexander‐Brett, J. M., Aschner, Y., Barczak, A. K., Basil, M. C., Cohen, K. A., Cruz, C. S. D., McGroder, C. F., Restrepo, M. I., et al. (2024) · Annals of the American Thoracic Society · doi:10.1513/annalsats.202406-651st · Cited by 28
“…of virus-induced immunopathology include hyperin fl ammation, hypercomplementemia, excessive neutrophil response and release of neutrophil extracellular traps (NETs), monocyte and macrophage activation, natural killer and CD8 T-cell alterations, endotheliitis, and immunothrombosis (146, 151).”
Li, S., Wang, H., & Shao, Q. (2023) · Immunity Inflammation and Disease · doi:10.1002/iid3.949 · Cited by 14
“SARS‐CoV‐2 activates pathogen recognition receptor signaling, resulting in the simultaneous release of IFNs and other proinflammatory cytokines.(21) Metabolites analysis revealed that neutrophils from SARS‐CoV‐2 patients have shown higher ROS emission.”
BackgroundUnderstanding immunity: an alternative framework beyond defense and strength
Zach, M., & Greslehner, G. P. (2023) · Biology & Philosophy · doi:10.1007/s10539-023-09893-2 · Cited by 35
“…enhanced—hence dysregulated—which, together with other age-related changes such as the shift in the relative numbers of some immune cell subsets and their phenotypes may, at least in part, explain why age is a major risk factor in COVID-19 (Brodin 2021; Schultze and Aschenbrenner 2021).10”
BackgroundAge-related changes in plasma biomarkers and their association with mortality in COVID-19
Michels, E. H. A., Appelman, B., de Brabander, J., van Amstel, R. V., Chouchane, O., van Linge, C. C. A., Schuurman, A., Reijnders, T., Sulzer, T. A. L., Klarenbeek, A. M., et al. (2023) · European Respiratory Journal · doi:10.1183/13993003.00011-2023 · Cited by 16
Toscano, E., Martínez‐Gallo, M., Arrese-Muñoz, I., Giné, A., Troyano, N. D., Gabriel-Medina, P., Riveiro‐Barciela, M., Labrador‐Horrillo, M., Martínez‐Valle, F., Sánchez‐Montalvá, A., et al. (2021) · BMC Medicine · doi:10.1186/s12916-022-02345-w · Cited by 14
Latifi-Pupovci, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113368 · Cited by 16
“are armed with an arsenal of PRRs that recognize PAMPs and home to the site of infection [37,38].”
Dean, L. S., Devendra, G., Jiyarom, B., Subia, N., Tallquist, M., Nerurkar, V. R., Chang, S. P., Chow, D., Shikuma, C., & Park, J. (2022) · bioRxiv · doi:10.3389/fimmu.2022.1076724 · Cited by 15
Mohamed, Y., El‐Maradny, Y. A., Saleh, A. K., Nayl, A. A., El‐Gendi, H., & El‐Fakharany, E. M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113499 · Cited by 20
“storm has been enlarged to cover any inflammatory disorders with high circulating cytokines that cause systemic inflammation and secondary organ dysfunction regardless of absolute cytokine concentrations [46].”
Identification of serum metabolites enhancing inflammatory responses in COVID-19
Zhang, C., Zhang, B., Li, M., Wei, X., Gong, K., Li, Z., Yao, X., Wu, J., Zhang, C., Zhu, M., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-021-2099-7 · Cited by 15
“…which is known as ‘‘cytokine storm’’, and is closely associated with patient mortality (Del Valle et al., 2020; Karki et al., 2021; Laing et al., 2020; Liu et al., 2020; Long et al., 2020; Mulchandani et al., 2021; Schultze and Aschenbrenner, 2021; Sette and Crotty, 2021; Wang et al., 2020b).”
Host factors of SARS-CoV-2 in infection, pathogenesis, and long-term effects
Zhang, Y., Chen, S., Tian, Y., & Fu, X. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1407261 · Cited by 16
“…and the activation of IFN signaling pathways in an autocrine and paracrine manner (Akira et al., 2006; Minkoff and tenOever, 2023), ultimately inducing hundreds of interferon-stimulated genes (ISGs) with various antiviral functions to foster an antiviral state (Schultze and Aschenbrenner, 2021).”
BackgroundAbdulla, Z. A., Al-Bashir, S. M., Alzoubi, H., Al-Salih, N. S., Aldamen, A. A., & Abdulazeez, A. Z. (2023) · Pathogens · doi:10.3390/pathogens12020329 · Cited by 13
Qian, G., Fang, H.-W., Chen, A., Sun, Z., Huang, M.-Y., Luo, M., Cheng, E.-D., Zhang, S.-Y., Wang, X., & Fang, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1257834 · Cited by 15
“Simultaneously, the release of in fl ammatory mediators like cytokines and chemokines can amplify the in fl ammatory response into a “ cytokine storm, ” potentially causing systemic in fl ammation that affects multiple organs (28, 44, 45, 47).”
BackgroundKumar, A., Tripathi, P., Kumar, P., Shekhar, R., & Pathak, R. (2024) · Vaccines · doi:10.3390/vaccines12050459 · Cited by 17
“SARS-CoV-2 infection triggers an excessive immune response in the host, resulting in an exaggerated inflammatory reaction characterized by the abundant production of various cytokines and chemokines by the host cells [152,153].”
BackgroundWang, X., Tan, X., Zhang, T., Xu, S., Zeng, Y., Xu, A., Li, X., Zhang, G., Jiang, Y., Jiang, H., et al. (2025) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2025.111421 · Cited by 12
SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity
Yu, S., Hu, H., Ai, Q., Bai, R., Ma, K., Zhou, M., & Wang, S. (2023) · Viruses · doi:10.3390/v15030639 · Cited by 20
“The host innate immune response serves as the initial defense against a broad range of pathogens and shapes an essential adaptive immune response to clear viral pathogens [147].”
BackgroundThe long Pentraxin PTX3 serves as an early predictive biomarker of co-infections in COVID-19
Scavello, F., Brunetta, E., Mapelli, S. N., Nappi, E., Martín, I. D. G., Sironi, M., Leone, R., Solano, S., Angelotti, G., Supino, D., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105213 · Cited by 14
de Campos‐Mata, L., Vaquero, S. T., Tachó‐Piñot, R., Piñero, J., Grasset, E. K., Arrieta‐Aldea, I., Melero, N. R., Carolis, C., Horcajada, J. P., Cerutti, A., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1339 · Cited by 17
“Acute SARS-CoV-2 infection triggers alterations in circulating innate immune cell subsets, some of which have been associated with COVID-19 severity.(41) Nevertheless, how these perturbations persist during convalescence after viral clearance is unclear.”
Should We Interfere with the Interleukin-6 Receptor During COVID-19: What Do We Know So Far?
Plocque, A., Mitri, C., Lefèvre, C., Tabary, O., Touqui, L., & Philippart, F. (2022) · Drugs · doi:10.1007/s40265-022-01803-2 · Cited by 12
“Therefore, tocilizumab may have a true therapeutic effect in this context, but the targeted patients, especially in terms of severity, remain very poorly defined [16, 24], and broad use is unquestionably expensive and irrelevant [101].”
BackgroundProtease inhibitor plasma concentrations associate with COVID-19 infection
Medjeral‐Thomas, N., Troldborg, A., Hansen, A. G., Pihl, R., Clarke, C., Peters, J. E., Thomas, D., Willicombe, M. K., Palarasah, Y., Botto, M., et al. (2021) · Oxford Open Immunology · doi:10.1093/oxfimm/iqab014 · Cited by 16
Identification of an immunological signature of long COVID syndrome
Guerrera, G., Sambucci, M., Timperi, E., Picozza, M., Misiti, A., Placido, R., Corbisiero, S., D’Orso, S., Termine, A., Fabrizio, C., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1502937 · Cited by 12
Immune response induced by novel coronavirus infection
Sun, Y., Zou, Y., Wang, H., Cui, G., Yu, Z., & Ren, Z. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.988604 · Cited by 20
“In rare cases, children develop childhood multisystemic inflammatory syndrome (MISC) 1-2 months after infection with SARS-CoV-2, which is similar to Kawasaki disease, with elevated inflammatory markers, fever and multiple organ dysfunction (Schultze and Aschenbrenner, 2021).”
BackgroundImmunoinflammation and post-translational modifications in the aging process
Xiao, J., Qin, X., Chen, W., Que, X., Ma, Y., Huang, W., Ou, H., Bao, Y., Qu, L., & Shan, S. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06892-7 · Cited by 15
“Immunosenescence manifests through progressive deterioration of immune components, encompassing both innate and adaptive immunity systems [37, 38].”
Bolesławska, I., Kowalówka, M., Bolesławska-Król, N., & Przysławski, J. (2023) · Viruses · doi:10.3390/v15061262 · Cited by 18
“The course of infection may also be influenced by the external environment and the virus itself due to its genetic diversity, genetic evolution, and variable infectivity [77].”
InfluentialWidder, S., Görzer, I., Friedel, B., Rahimi, N., Schwarz, S., Jaksch, P., Knapp, S., & Puchhammer-Stöckl, E. (2022) · Microbiome · doi:10.1186/s40168-022-01244-9 · Cited by 14
Luedemann, M., Stadler, D., Cheng, C., Protzer, U., Knolle, P. A., & Donakonda, S. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.01.024 · Cited by 27
“SARS-CoV-2 is known to trigger innate immune cell activation [48].”
Zhao, X., Chen, D., Li, X., Griffith, L. E., Chang, J., An, P., & Guo, J. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167438 · Cited by 15
“Transcriptional activation of IRF3/7 and NF-κB coordinately induces the expression of type I and type III IFNs to restrict viral replication as well as inflammatory cytokines and chemokines to recruit specific subsets of leukocytes and facilitate the activation of adaptive immune responses for the resolution of viral…”
BackgroundInfection‐induced inflammation from specific inborn errors of immunity to COVID‐19
Ku, C., Chen, I., & Lai, M. (2021) · FEBS Journal · doi:10.1111/febs.15961 · Cited by 11
van der Straten, K., van Gils, M. J., de Taeye, S. W., & de Bree, G. J. (2022) · Frontiers in Medical Technology · doi:10.3389/fmedt.2022.867982 · Cited by 17
“The innate immune system has a prominent role at the start of an infection as it acts as one of the first defense mechanisms against pathogens (108).”
BackgroundDixit, S., Borghi-Silva, A., Gular, K., Reddy, R. S., Kakaraparthi, V., Ribeiro, I. L., Tedla, J., & Girish, S. (2022) · Heart & lung : the journal of critical care · doi:10.1016/j.hrtlng.2022.09.019 · Cited by 14
“It typically comprises immune cell-like monocytes, macrophages, granulocytes, and NK cells (26).”
BackgroundMovassagh, M., Morton, S. U., Hehnly, C., Smith, J., Doan, T. T., Irizarry, R. A., Broach, J. R., Schiff, S. J., Bailey, J. A., & Paulson, J. N. (2022) · BMC Genomics · doi:10.1186/s12864-022-08558-w · Cited by 17
“It has been argued that differences in the innate immune response are responsible for the heterogeneity of outcomes after SARS-CoV-2 infection [57].”
BackgroundInnate and Adaptive Immune Assessment at Admission to Predict Clinical Outcome in COVID-19 Patients
Segundo, D. S., Revillas, F. A. D. L., Lamadrid-Perojo, P., Comins‐Boo, A., González-Rico, C., Alonso‐Peña, M., Irure‐Ventura, J., Olmos, J. M., Fariñas, M. C., & López‐Hoyos, M. (2021) · Biomedicines · doi:10.3390/biomedicines9080917 · Cited by 14
“The in ate immune system is involve in the first stage of any viral infection, including COVID-19 disease [16].”
BackgroundInfluentialYounger Children Develop Higher Effector Antibody Responses to SARS-CoV-2 Infection
Tomasi, L., Thiriard, A., Heyndríckx, L., Georges, D., den Wijngaert, S. V., Olislagers, V., Sharma, S., Matagne, A., Ackerman, M. E., Ariën, K. K., et al. (2022) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofac554 · Cited by 14
“Innate immunity involving type I interferons is essential for the control of SARS-CoV-2 replication during the early phase of the infection, whereas excessive innate immune responses play a pathogenic role later in the course of COVID-19 [12].”
BackgroundPersonalized health and the coronavirus vaccines—Do individual genetics matter?
Valdés‐Fernández, B. N., Duconge-Soler, J., Espino, A. M., Ruaño, G., Campus, P., Juan, S., & Rico, P. (2021) · BioEssays · doi:10.1002/bies.202100087 · Cited by 16
Lesseur, C., Jessel, R., Ohrn, S., Ma, Y.-L., Li, Q., Dekio, F., Brody, R., Wetmur, J., Gigase, F., Lieber, M., et al. (2022) · medRxiv · doi:10.1016/j.placenta.2022.06.017 · Cited by 13
“Although comprehensive knowledge of the factors involved in severe Covid-19 is still needed, dysregulation of the host inflammatory and immune responses [4,5] and thrombosis [6] have been implicated in Covid-19 induced tissue damage.”
BackgroundJeong, H., Lee, J. S., Ko, J., Hong, S., Oh, S. T., Choi, S., Peck, K. R., Yang, J. H., Chung, S. H., Kim, S., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-00964-8 · Cited by 17
Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative?
Palacios, Y., & Chávez‐Galán, L. (2022) · Pharmaceuticals · doi:10.3390/ph15050616 · Cited by 15
Evaluating the Immune Response in Treatment-Naive Hospitalised Patients With Influenza and COVID-19
Legebeke, J., Lord, J., Penrice-Randal, R., Vallejo, A. F., Poole, S., Brendish, N. J., Dong, X., Hartley, C. S., Holloway, J. W., Lucas, J. S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.853265 · Cited by 18
“This is similar to findings of positive regulation of genes encoding the activation of innate immune system, viral and IFN response (1), increase of proinflammatory macrophages (65) and elevated IL-6 and IL-10 in severe COVID-19 cases (12–14).”
ResultVicentino, A. R., Fraga-Junior, V. D. S., Palazzo, M., Tasmo, N. R. A., Rodrigues, D. A., Barroso, S., Ferreira, S., Neves-Borges, A. C., Allonso, D., Fantappié, M., et al. (2023) · Clinical and Translational Science · doi:10.1111/cts.13475 · Cited by 13
Human coronaviruses: activation and antagonism of innate immune responses
Tanneti, N. S., Stillwell, H. A., & Weiss, S. R. (2024) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00016-23 · Cited by 14
“SARS-CoV-2 provokes a moderate IFN response, and a muted and/or delayed IFN response was shown to be associated with more severe disease in COVID-19 patients (160).”
Mitochondrial dysfunction at the cornerstone of inflammatory exacerbation in aged macrophages
Maurmann, R. M., Schmitt, B. L., Mosalmanzadeh, N., & Pence, B. D. (2023) · Exploration of Immunology · doi:10.37349/ei.2023.00112 · Cited by 12
Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality
Albert, M., Uranga-Murillo, I., Arias, M. A., de Miguel, D., Peña, N., Montinaro, A., Varanda, A. B., Theobald, S. J., Zubiaur, I. A., Saggau, J., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01278-6 · Cited by 15
“Correspondingly, SARS-CoV-2-induced lung failure is associated with an in fl ux of neutrophils and in fl ammatory macrophages into the lungs, which is accompanied by an increase in cytokines and chemokines of the innate immune system [9, 10].”
BackgroundKim, H., Choi, H.-G., & Shin, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1193058 · Cited by 13
SARS-CoV-2 versus Influenza A Virus: Characteristics and Co-Treatments
Wang, X., Li, J., Liu, H., Hu, X., Lin, Z., & Xiong, N. (2023) · Microorganisms · doi:10.3390/microorganisms11030580 · Cited by 17
“After the virus crosses the mucus barriers, pathogen-associated molecular patterns (PAMPs), containing molecular structures that are found in microbes but not in hosts, are identified by the host’s pattern recognition receptors (PRRs) including toll-like receptor (TLR), retinoic acid-inducible gene I (RIG-I) and melan…”
BackgroundZepeda–Cervantes, J., Martínez-Flores, D., Ramírez‐Jarquín, J. O., Tecalco-Cruz, Á. C., Alavez-Pérez, N. S., Vaca, L. A., & Silva, R. E. S. (2022) · Viruses · doi:10.3390/v14010094 · Cited by 17
The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics
Nguyen, H. T. T., Do, V., Phan, T. T., & Huynh, D. T. N. (2023) · Bioinformatics and Biology Insights · doi:10.1177/11779322221149622 · Cited by 12
Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus
Kleijwegt, C., Bressac, F., Cohen, C., Texier, P., Simonet, T., Schaeffer, L., Lomonte, P., & Corpet, A. (2021) · bioRxiv · doi:10.1101/2021.11.30.470516 · Cited by 12
DNA repair and disease: insights from the human DNA glycosylase NEIL family
Hwang, Y., Kang, S.-J., Kang, J., Choi, J., Kim, S.-J., & Jang, S. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01417-0 · Cited by 18
“Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the expression of soluble in fl ammatory mediators, leading to the in fl ux of in fl ammatory cells, such as macrophages, T cells and neutrophils, to the infection site 63,64 .”
Art–science multidisciplinary collaborations to address the scientific challenges posed by COVID-19
de la Fuente, J. (2022) · Annals medicus · doi:10.1080/07853890.2022.2123557 · Cited by 12
Robertson, S. J., Bedard, O., McNally, K. L., Shaia, C., Clancy, C. S., Lewis, M. C., Broeckel, R. M., Chiramel, A. I., Shannon, J. G., Sturdevant, G. L., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40076-5 · Cited by 28
Aljuhani, A., Albalawi, O., Albalawi, R., Alsalama, R., Alatawi, S., Altemani, R., Abdel‐Maksoud, M. S., & Elsherbiny, N. (2023) · Cell Biology International · doi:10.1002/cbin.12014 · Cited by 12
“…production, impairing adaptive immunity, while nonstructural proteins act as ribosome gatekeeper to specifically promote viral translation and inhibit cellular translation, diminish viral RNA recognition by intracellular helicase receptors (Schultze & Aschenbrenner, 2021) (Tidu et al., 2020).”
BackgroundCOVID-19: Not a thrombotic disease but a thromboinflammatory disease
He, S., Blombäck, M., & Wallén, H. (2024) · Upsala Journal of Medical Sciences · doi:10.48101/ujms.v129.9863 · Cited by 12
“This process may amplify oxidative stress, cytokine release, and the release of procoagulant molecules, creating a pro-thrombotic environment (124–126 (133).”
BackgroundCOVID‐19, obesity, and immune response 2 years after the pandemic: A timeline of scientific advances
Belchior‐Bezerra, M., Lima, R. S., Medeiros, N. I., & Gomes, J. D. A. S. (2022) · Obesity Reviews · doi:10.1111/obr.13496 · Cited by 16
Fu, Z.-Y., Liang, D.-G., Zhang, W., Shi, D., Ma, Y., Wei, D., Xi, J., Yang, S.-Z., Xu, X., Tian, D., et al. (2023) · Frontiers in Medicine · doi:10.1007/s11684-022-0977-3 · Cited by 12
“), the changing landscape of the Omicron genome arouses considerable uncertainty as to whether more transmissible and virulent strains would emerge in the coming waves of the pandemic [7], making it necessary to closely monitor and investigate the clinical features of SARS-CoV-2 subvariants over time, evaluate the ben…”
BackgroundPotential mechanism of SARS‐CoV ‐2‐associated central and peripheral nervous system impairment
Zhang, Y., Chen, X., Jia, L., & Zhang, Y. (2022) · Acta Neurologica Scandinavica · doi:10.1111/ane.13657 · Cited by 13
LAG-3 Contribution to T Cell Downmodulation during Acute Respiratory Viral Infections
Rodríguez‐Guilarte, L., Ramírez, M. A., Andrade, C. A., & Kalergis, A. M. (2023) · Viruses · doi:10.3390/v15010147 · Cited by 11
“SARS-CoV-2 is the viral pathogen responsible for the 2019 pandemic and the etiological agent for Coronavirus disease 2019 (COVID-19) [85].”
InfluentialZhang, C., Min, Y.-Q., Xue, H., Zhang, H.-Y., Liu, K.-P., Tian, Y., Yang, Z., Zhao, Z., Yang, H., Chao, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61431-8 · Cited by 12
Global Gene Expression and Docking Profiling of COVID-19 Infection
Jabeen, A., Ahmad, N., & Raza, K. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.870836 · Cited by 20
“COVID-19 symptoms range from mild to severe disease, and the explanation of this variation in infection response is unknown (Hu et al., 2020; Hartung and Aktas 2020; Hirano and Murakami 2020; de las Heras et al., 2020; Schultze and Aschenbrenner 2021; Tay et al., 2020).”
BackgroundYuan, C., Xiao, Q.-C., Chen, Q.-H., Huang, Q., Ai, K., & Yang, X.-Y. (2024) · SmartMat · doi:10.1002/smm2.1264 · Cited by 12
Hollenberg, M. D., & Epstein, M. (2022) · Kidney International Supplements · doi:10.1016/j.kisu.2021.12.001 · Cited by 16
“Kidney International Supplements (2022) 12, 48–62 associated molecular patterns (which activate patternrecognition receptors, such as membrane-bound Toll-like receptors) typically are thought to play a key role in innate immunity, their involvement in the rapid innate response to COVID-19 infection is not yet fully un…”
Hall, S., Faridi, S., Trivedi, P., Sultana, S., Ray, B., Myers, T., Euodia, I., Vlatten, D., Castonguay, M., Zhou, J., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415857 · Cited by 11
“Sci. 2022, 23, 15857 2 of 19 The pathophysiology underlying ARDS is generally termed acute lung injury (ALI) [9] and is heavily derived from pulmonary innate immune responses [10].”
BackgroundInfluentialDeval, H., Nyayanit, D. A., Mishra, S., Yadav, P., Zaman, K., Shankar, P., Misra, B., Behera, S., Kumar, N., Kumar, A., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2021.781287 · Cited by 11
“Hence, the whole genome sequence (WGS) analysis has become an important tool for understanding the evolution of COVID-19 lineages and emphasizing the discovery of potent gene-mediated pathways associated with the onset of the disease in humans (6).”
BackgroundTargeting intracellular Neu1 for coronavirus infection treatment
Yang, D., Wu, Y., Turan, I. M., Keil, J. M., Li, K., Chen, M. H., Liu, R., Wang, L., Sun, X., & Chen, G. (2023) · iScience · doi:10.1016/j.isci.2023.106037 · Cited by 12
Mutational Landscape and Interaction of SARS-CoV-2 with Host Cellular Components
Srivastava, M., Hall, D., Omoru, O. B., Gill, H. M., Smith, S., & Janga, S. C. (2021) · Microorganisms · doi:10.3390/microorganisms9091794 · Cited by 13
“Several of the viral non-structural proteins (Orf6, Orf9, Nsp13, and Nsp15) targets proteins of the IFN pathway, resulting in a dysregulated immune response [77,88,89].”
BackgroundChakraborty, C., Bhattacharya, M., & Lee, S. (2024) · Reviews in Medical Virology · doi:10.1002/rmv.2526 · Cited by 14
“108 Similarly, it was also illustrated that cytokine storm and inflammation were noted in the worse clinical outcomes during SARS ‐ CoV ‐ 2 infection.”
BackgroundLiang, J.-B., & Yuan, H.-Y. (2021) · medRxiv · doi:10.1016/j.envres.2022.112931 · Cited by 11
Khare, K., & Pandey, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.973070 · Cited by 15
“The innate immune cells are the primary target for successful SARS-CoV-2 infection (29).”
BackgroundLi, Y.-Y., Yuan, M., Li, S., Wang, J.-D., Wang, Y.-F., Li, Q., Li, J., Chen, R.-R., Peng, J.-M., & Du, B. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01645-7 · Cited by 11
“Adaptive immunity, including B cells and T cells, starts participating in the antiviral process a few days after infection [28].”
BackgroundGut microbiota composition is associated with disease severity and host immune responses in COVID-19
Fan, R., Liu, S., Sun, N., Yang, Y., Deng, X., Hu, B., Sun, C., Wen, C., Li, H., Cheng, D., et al. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1274690 · Cited by 12
“When the virus enters a cell, it has the potential to trigger innate and adaptive host immune responses, which are essential parts of the defense against viral infections (Schultze and Aschenbrenner, 2021; Sette and Crotty, 2021).”
Inverse Association between Omega-3 Index and Severity of COVID-19: A Case–Control Study
Ramírez-Santana, M., Barra, R. Z., González, M. Ñ., Müller, J., Vásquez, J., Ravera, F., Lago, G., Cañón, E., Castañeda, D., & Pradenas, M. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19116445 · Cited by 11
“Thus, a coordinated local and systemic immune response may be crucial to prevent the more severe spectrum of COVID-19 [29,30].”
BackgroundMaquet, C., Baiwir, J., Loos, P., Rodriguez-Rodriguez, L., Javaux, J., Sandor, R., Perin, F., Fallon, P. G., Mack, M., Cataldo, D. D., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn3240 · Cited by 11
“Variability in innate immune responses is one of the main factors associated with diverse disease responses to respiratory viral infections (3).”
BackgroundInsertion/deletion hotspots in the Nsp2, Nsp3, S1, and ORF8 genes of SARS-related coronaviruses
Akaishi, T., Fujiwara, K., & Ishii, T. (2022) · BMC Ecology and Evolution · doi:10.1186/s12862-022-02078-7 · Cited by 11
How is the behavioral immune system related to hygiene behaviors?
Wormley, A. S., & Varnum, M. E. W. (2022) · Current Research in Ecological and Social Psychology · doi:10.1016/j.cresp.2022.100081 · Cited by 12
When RING finger family proteins meet SARS‐CoV‐2
Cai, C., Tang, Y., & Zheng, C. (2022) · Journal of Medical Virology · doi:10.1002/jmv.27701 · Cited by 11
“The sensing of viral RNA induces IFN‐I and proinflammatory cytokines production via TBK1‐IRF3/7 and TAK1‐IKK‐NF‐κB axis, resulting in hundreds of IFN‐stimulated genes (ISGs) production to affect the action of the ensuing adaptive immune response and the eventual virus elimination.(3,47) SARS‐CoV‐2 elicits both cellula…”
BackgroundIL-1β drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling
Bader, S. M., Scherer, L., Schaefer, J., Cooney, J. P., Mackiewicz, L., Dayton, M., Georgy, S. R., Davidson, K. C., Allison, C. C., Herold, M. J., et al. (2025) · Cell Death and Differentiation · doi:10.1038/s41418-025-01459-x · Cited by 13
“Results are pooled from 2 independent experiments ( n = 12 – 15 mice per genotype).”
Ford, M., Hari, A., Rodriguez, O. L., Xu, J., Lack, J., Oguz, C., Zhang, Y., Oler, A. J., Delmonte, O., Weber, S., et al. (2022) · Cell Systems · doi:10.1016/j.cels.2022.08.008 · Cited by 11
Harnessing traditional Chinese medicine polysaccharides for combatting COVID-19
Xiao, Z., Guo, Y., Li, J., Jiang, X., Wu, F., Wang, Y., Zhang, Y., & Zhou, W. (2024) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2024.122605 · Cited by 12
Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever
Kharouf, F., Ishay, Y., Kenig, A., Bitan, M., & Ben-Chetrit, E. (2021) · Rheumatology · doi:10.1093/rheumatology/keab577 · Cited by 11
Advances in understanding the role of pentraxin-3 in lung infections
Ma, L., Li, D.-M., Wen, Y.-Y., & Shi, D.-M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1575968 · Cited by 11
“SARS-CoV-2, the virus responsible for the COVID-19 pandemic, elicits a robust immune response of the innate immune system (82, 83).”
Binayke, A., Zaheer, A., Dandotiya, J., Gupta, S. K., Mani, S., Tripathi, M., Madan, U., Shrivastava, T., Kumar, Y., Pandey, A. K., et al. (2022) · Vaccines · doi:10.3390/vaccines10101762 · Cited by 12
Silva, B. R., Monteiro, F. R., Cezário, K., do Amaral, J. B., Paixão, V., Almeida, E. B., Santos, C. A. F., Amirato, G. R., Oliveira, D. B. L., Durigon, E. L., et al. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20031939 · Cited by 12
“However, it is known that the severity of COVID-19 can be closely associated not only with some clinical conditions of the individual infected by the SARS-CoV-2 virus but also with an exacerbated immune/inflammatory reaction to this infection, which induces a systemic hyperinflammatory response known as the “Cytokine…”
BackgroundVaccines for Respiratory Viruses—COVID and Beyond
Rajanala, K., & Upadhyay, A. (2024) · Vaccines · doi:10.3390/vaccines12080936 · Cited by 10
“Once inside the cell, the viral RNA is sensed by the pattern recognition receptors (PRRs), such as retinoic acid-inducible gene 1 (RIG-I) and Toll-like receptors (TLRs) [59] (Figure 2).”
BackgroundVeizades, S. A., Tso, A., & Nguyen, P. K. P. (2021) · Biological Chemistry · doi:10.1515/hsz-2021-0348 · Cited by 12
Miao, J., Gu, X.-Y., & Shi, R.-Z. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.974944 · Cited by 10
“COVID-19-induced clinical manifestations range from asymptomatic latent infection to severe pneumonia with respiratory failure, multi-organ failure, and rapid death (1, 2).”
BackgroundDashatan, N. A., Koushki, M., & Rezaei–Tavirani, M. (2022) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2021.0182 · Cited by 11
“IP-1 , MCP-1 , and TNF-a (Schultze and Aschenbrenner, 2021).”
Rodríguez‐Ubreva, J., Calafell-Segura, J., Calvillo, C. L., Keller, B., Ciudad, L., Handfield, L., de la Calle‐Fabregat, C., Godoy‐Tena, G., Andrés‐León, E., Hoo, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54732-x · Cited by 14
“Therefore, effective immune responses against SARS-CoV-2 requirethat the host ’ s immune system provides a balanced and coordinated response involving both innate and adaptive immune systems 13,14 .”
Pinacchio, C., Scordio, M., Santinelli, L., Frasca, F., Sorrentino, L., Bitossi, C., Oliveto, G., Viscido, A., Ceci, F. M., Celani, L., et al. (2022) · Journal of immunoassay & immunochemistry · doi:10.1080/15321819.2022.2035394 · Cited by 10
“However, it is known that the underlying molecular biology of COVID-19 involves complex interactions between networks of genes, inflammatory signaling pathways, and gene regulatory mechanisms,([61]) and a better understanding of these molecular processes is essential for translational research.”
BackgroundHasan, A., Rahim, R., Nakayama, E., Uno, K., Hasan, N., Rahman, M., & Shioda, T. (2023) · Viruses · doi:10.3390/v15102018 · Cited by 10
“During SARS-CoV-2 infection, host cells produce numerous cytokines and chemokines to initiate inflammatory responses and to mediate innate immune responses [17,18].”
BackgroundFarmani, A. R., Swanson, R., Mahdavinezhad, F., Shoormeij, M., Mohammadi, S., Moeinzadeh, A., Ghazipour, F., & Ai, J. (2021) · Journal of New Materials for Electrochemical Systems · doi:10.14447/jnmes.v24i4.a10 · Cited by 10
Wu, X.-S., Manske, M., Ruan, G. J., Witter, T. L., Nowakowski, K., Abeykoon, J., Tang, X.-Y., Yu, Y., Gwin, K. A., Wu, A., et al. (2021) · bioRxiv · doi:10.1101/2021.12.02.470978 · Cited by 10
“Numerous studies have shown that the 42 production of pro-inflammatory cytokines including IL1b, IL6, IL8, IL18, and CCL2, is 43 responsible for the life-threatening symptoms, and the levels of these cytokines 44 correlate with disease severity.(2,3) It has also been demonstrated that the virus primarily 45 targets na…”
BackgroundRNA editing regulates host immune response and T cell homeostasis in SARS-CoV-2 infection
Huang, M., Mark, A., Pham, J., Vera, K., Saravia-Butler, A. M., Beheshti, A., Jiang, Q.-F., & Fisch, K. M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0307450 · Cited by 10
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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