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Cited by 714SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research Studiesinterferon and immune responses

COVID-19 and the human innate immune system

Open access
Schultze, Joachim L., Aschenbrenner, Anna C.·2021·Cell
DOI 10.1016/j.cell.2021.02.029PMC PMC7885626
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Abstract

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.

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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.

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Integrity signals

Registry

Crossref · 10.1016/j.cell.2021.02.029

Cites

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Claims the paper makes

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  • Premisecitation

    The D614G spike protein variant of SARS-CoV-2 increased infectivity.

    “Although many mutations decreased infectivity, the virus variant D614G in the spike protein of SARS-CoV-2 increased infectivity (Li et al., 2020).”
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    The 2009 influenza pandemic had much lower incidence in elderly people, indicating partial population-level protection from earlier exposure to similar influenza viruses.

    “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).”
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  • Interpretationcitation

    Cross-protection via adaptive immune responses against endemic coronaviruses might partly explain mild COVID-19 in younger individuals.

    “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).”
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    SARS-CoV-2 employs the cellular serine protease TMPRSS2 for S protein priming.

    “Similar to SARS-CoV (Matsuyama et al., 2010), SARS-CoV-2 employs the cellular serine protease TMPRSS2 for S protein priming.”
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    Metadata analysis of many scRNA-seq datasets can predict the impact of clinical risk factors such as sex, age, and smoking history on expression of genes associated with viral entry.

    “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.”
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    Premisenone given

    Innate immunity serves as the first line of host defense and is central in fighting SARS-CoV-2.

    “Innate immunity—as the first line of defense of our immune system—plays a central role in combating this novel virus.”
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    Premisecitation

    COVID-19 is heterogeneous, with courses from asymptomatic or mild to severe or critical in 10%-20% of symptomatic patients, who face substantial fatality risk and involvement of multiple organ systems.

    “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)”
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    Premisecitation

    TMPRSS2 is more widely expressed than ACE2, and cells with simultaneous expression occur in the respiratory tree, cornea, esophagus, ileum, colon, gallbladder, and common bile duct, with no evidence for simultaneous expression in immune cells.

    “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.”
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    Interpretationcitation

    COVID-19 severity and mortality are significantly higher in elderly populations, pointing toward a lack of widespread long-lasting pre-existing adaptive immunity by T or B cells against SARS-CoV-2.

    “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).”
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    In vitro monocyte-derived macrophages and dendritic cells are susceptible to SARS-CoV-2 infection, but the infection is abortive because these cells do not support virus replication.

    “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).”
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    Premisecitation

    The virus, the environment, and the host can each contribute to COVID-19 disease heterogeneity.

    “The virus itself, the environment, and the host can contribute to such disease heterogeneity (Morens and Fauci, 2020).”
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    Premisecitation

    Viral genetic diversity, evolution, variable infectivity, or co-pathogenesis might contribute to infectivity and fatality but not much to COVID-19 disease heterogeneity.

    “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.”
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    Interpretationcitation

    Nasal epithelial cells co-express genes involved in early antiviral immune responses, indicating that these specialized cells may play an important role in initial viral infection, spread, and potentially clearance.

    “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.”
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    Premisecitation

    Environmental factors such as seasonality, natural disasters, environmental degradation, public health infrastructure, and governance affect overall disease burden for society.

    “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)”
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    DeltaACE2 neither binds the SARS-CoV-2 spike protein nor serves as a carboxypeptidase.

    “DeltaACE2 neither binds the SARS-CoV-2 spike protein nor serves as a carboxypeptidase.”
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    There has been no evidence for a role of innate immune cells in SARS-CoV-2 gaining access to the retina or the brain, although the virus has been found in both organs.

    “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.”
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    Interpretationcitation

    The host appears to be the major factor explaining COVID-19 disease severity, infection rates, and long-term medical consequences.

    “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).”
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    Premisecitation

    The human placenta is highly susceptible to SARS-CoV-2 infection, but only non-immune cells, including first-trimester syncytiotrophoblasts and second-trimester extravillous trophoblasts, express ACE2 and TMPRSS2 and are cellular targets for the virus.

    “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).”
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    ACE2 and TMPRSS2 are expressed on platelets, and patients present with signs of platelet hyperactivation, particularly in severe COVID-19.

    “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).”
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    Premisecitation

    In a murine model of SARS-CoV-2 infection, type I IFNs do not control SARS-CoV-2 replication in vivo but are significant drivers of pathologic responses.

    “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).”
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    Premisecitation

    Functional testing supported the counteracting activity of ORF3b, ORF6, NSP1, or NSP13 on type I IFN activation, with ORF6 particularly suppressing STAT1 and STAT2 phosphorylation and STAT1 nuclear translocation.

    “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).”
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    Premisecitation

    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.

    “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).”
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    Interpretationcitation

    CD147 is widely expressed and receptor expression does not seem to correlate with viral load, arguing against CD147 as a major entry receptor for SARS-CoV-2.

    “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.”
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    Premisecitation

    In vitro exposure to SARS-CoV-2 or its Spike protein potentiated platelet aggregation, dense granule release, upregulation of activation markers, platelet spreading, and clot retraction.

    “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.”
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    Interpretationcitation

    Other coronavirus receptors (ANPEP and DPP4) and several proteases (CTSL, CTSB, and Furin) are uniformly expressed in the placenta during the first and second trimesters, and genes needed for viral budding and replication are present, suggesting the placenta is vulnerable to productive infection.

    “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).”
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    Premisecitation

    A common pattern of coronavirus cell entry via endocytosis after receptor binding is followed by viral RNA release into the cytoplasm, production of viral proteins, and formation of viral replication/transcription complexes on double-membrane vesicles.

    “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).”
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    Premisecitation

    NSP16 suppresses global mRNA splicing and diminishes recognition of viral RNA by intracellular helicase receptors; NSP1 inhibits mRNA translation by binding 18S ribosomal RNA; NSP8 and NSP9 interfere with protein trafficking to the cell membrane; all three mechanisms independently reduce type I IFN production.

    “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”
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    Interpretationreasoning

    Detection of viral RNA in myeloid cells from lung or BALF of severe COVID-19 patients allows several explanations, including phagocytosis of cellular material from infected cells.

    “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.”
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    Premisecitation

    A current model holds that SARS-CoV-2 enters type II pneumocytes via ACE2, causing rapid replication and a proinflammatory state with elevated IL-1, IL-6, CXCL8, and TNF.

    “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”
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    Premisecitation

    Interaction mapping suggested that NSP13 interacts with TBK1, NSP15 with NRDP1, ORF9b with TOMM70, and ORF6 with KPNA2 or the IFN-induced NUP98-RAE1 nuclear export complex, all antagonizing IFN signaling.

    “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”
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    Interpretationcitation

    The pattern recognition receptors involved in recognizing SARS-CoV-2 are not yet directly determined; based on other coronaviruses, the most likely candidates are endosomal TLR3 and TLR7 or cytosolic RIG-I and MDA5.

    “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”
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    Premisecitation

    In in vitro infection models using cell lines, SARS-CoV-2 induced only low type I and II IFNs, consequently inducing moderate levels of ISGs and a unique proinflammatory cytokine signature including IL1B, IL6, TNF, and many chemokines.

    “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).”
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    Interpretationcitation

    NF-κB-dependent proinflammatory mediators can drive accumulation of pathogenic neutrophils and macrophages in the lung, perpetuating cytokine and chemokine elevation in BALF and circulation.

    “Accumulation of NF-κB-dependent proinflammatory mediators can provoke an accumulation of pathogenic inflammatory neutrophils and macrophages in the lung”
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    Premisecitation

    RIG-I and MDA5 trigger MAVS on mitochondria, then TRAF3, TBK1, and IKK, leading to phosphorylation of IRF3 and IRF7 and transcription of type I IFNs and numerous ISGs.

    “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”
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    Premisecitation

    COVID-19 patients showed a lack of expression of genes encoding type I IFNs in PBMCs 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.

    “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).”
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    Premisecitation

    Similar signaling cascades are known downstream of TLR3 and TLR7.

    “Similar signaling cascades are known downstream of TLR3 and TLR7 (Figure 2C).”
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    Premisecitation

    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.

    “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).”
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    Interpretationcitation

    SARS-CoV-2 facilitates release of coagulation factors, secretion of inflammatory cytokines, and formation of leukocyte-platelet aggregates, which might be important mechanisms leading to thromboembolic complications in severe COVID-19.

    “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).”
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    Premisecitation

    The type I IFN response can be heterogeneous: it depends on the reacting cell's state, is at least partly stochastic, varies among cell types and microenvironments, and shows interindividual heterogeneity in amplitude and kinetics.

    “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”
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    Interpretationcitation

    SARS-CoV-2 uses a multipronged strategy to antagonize the IFN system, with the clinical consequence of an insufficient type I IFN response in early COVID-19.

    “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).”
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    Interpretationcitation

    Early type I IFN treatment may help patients whose IFN system has genetic defects, but not those with autoimmune mimics of such defects.

    “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).”
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    Interpretationcitation

    Innate immune cells are differently programmed in mild versus severe COVID-19, with corresponding differences in adaptive immunity.

    “a scenario emerges with rather differently programmed innate immune cells in mild versus severe disease courses”
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    Interpretationcitation

    Circulating immune measures could help classify disease or forecast outcomes.

    “suggesting that immune parameters might be used for disease classification or outcome prediction.”
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    Interpretationcitation

    Complement components and regulators are elevated in severe COVID-19, pointing to complement activation as an early innate immune mechanism.

    “point toward complement activation as an early innate immune activation mechanism”
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    Interpretationreasoning

    Severe COVID-19 is better summarized as viral sepsis with immune deviation, where proinflammatory mediator upregulation is only one part of a derailed innate immune response.

    “better summarized as viral sepsis, with the upregulation of proinflammatory mediators being only one part of a derailed innate immune response”
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    Premisecitation

    In 1,484 COVID-19 patients, TNF, IL-1β, and IL-6 were elevated, and TNF and IL-6 independently predicted disease severity and death.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Del Valle et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Host genetics contribute to COVID-19 susceptibility and severity.

    “suggested that host genetics might contribute to disease susceptibility and severity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ovsyannikova et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trained immunity is a specialized form of innate immune memory, best characterized for BCG vaccination and β-glucan stimulation.

    “A specialized form of innate immune adaptation is the induction of immune memory (also termed trained immunity)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Netea et al., 2020a

      Not checked in the free run.

    • cites Giamarellos-Bourboulis et al., 2020b

      Not checked in the free run.

    • cites Moorlag et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammaging is a chronic sterile inflammation with elevated IL-6, TNF, CXCL8, CCL2, CRP, and PLA2GD, linked to reduced myeloid DC and pDC numbers and function.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Franceschi et al., 2017 source

      Not checked in the free run.

    • cites Frasca and Blomberg, 2016

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Mild COVID-19 features circulating HLA-DRhi CD11chi inflammatory monocytes with an interferon-stimulated gene signature, while severe cases show neutrophil precursors and dysfunctional PD-L1-expressing mature neutrophils.

    “Mild COVID-19 patients were marked by circulating HLA-DR hi CD11c hi inflammatory monocytes with an interferon-stimulated gene signature”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schulte-Schrepping et al., 2020 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    pDCs are reduced and functionally impaired in COVID-19, suggesting the lung is a source of elevated plasma type I IFNs early in infection.

    “suggesting the lung as a source for the elevated plasma levels of type I IFNs early on infection”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kuri-Cervantes et al., 2020 source

      Not checked in the free run.

    • cites Arunachalam et al., 2020 source

      Not checked in the free run.

    • cites Lucas et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Severe COVID-19 is characterized by increased circulating neutrophils and decreased lymphocytes.

    “An increase in circulating neutrophils versus a decrease in lymphocytes has been appreciated as a hallmark of severe COVID-19”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hadjadj et al., 2020 source

      Not checked in the free run.

    • cites Mathew et al., 2020 source

      Not checked in the free run.

    • cites Qin et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long COVID-19 can involve chronic fatigue syndrome and psychiatric problems such as cognitive decline, depression, and neurodegeneration.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Salisbury, 2020 source

      Not checked in the free run.

    • cites Taquet et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Icatibant for the kallikrein-kinin system and anti-C5a/C3a antibodies for coagulation have been proposed to ease symptoms and lower death rates.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites van de Veerdonk et al., 2020 source

      Not checked in the free run.

    • cites Mastellos et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Baricitinib also reduced proinflammatory cytokine production by lung macrophages and neutrophil recruitment into the lung.

    “suppressed the production of proinflammatory cytokines in lung macrophages, and the recruitment of neutrophils to the lung (Hoang et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoang et al., 2021 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Predicting drug responses from molecular data could support precision medicine after patients are stratified.

    “Further, molecular prediction of drug responses may guide the way for precision medicine approaches following patient stratification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Randomized trials showed dexamethasone lowered 28-day death rates, especially in severe cases.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites RECOVERY Collaborative Group et al., 2021

      Not checked in the free run.

    • cites Tomazini et al., 2020 source

      Not checked in the free run.

    • cites WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    COVID-19 studies have measured various soluble factor panels, but few used comprehensive approaches.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Messner et al., 2020 source

      Not checked in the free run.

    • cites Su et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An unknown proportion of patients will develop Long COVID-19, a chronic condition with diverse symptoms.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Marshall, 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    By late 2020, two mRNA vaccines had been authorized in the US, UK, Israel, and EU, with millions vaccinated.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Anderson et al., 2020 source

      Not checked in the free run.

    • cites Polack et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Viral sepsis may follow different paths in patients with COPD versus obesity, possibly needing different treatments.

    “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.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Early-phase measurable factors could help forecast viral sepsis outcomes.

    “Parameters measurable at earlier phases of the disease would be useful to predict the outcome of viral sepsis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    New therapies require clearer knowledge of the molecular immune events at the shift from local to systemic disease and during viral sepsis.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The roles of NK cells, innate lymphoid cells, mast cells, basophils, and eosinophils in COVID-19 remain insufficiently studied.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The organs affected, symptom severity, and duration of this phase vary widely.

    “Organ involvement, magnitude of clinical symptoms, and length of this phase is highly variable”
    Quote in the paperNot a substantial claim
60 of 60

  • 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”
4 of 4

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?

  • SARS-CoV-2 evades innate immunity through several mechanisms, suggesting innate responses are probably essential for protection.

    “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]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. de Chaisemartin, 2020, BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden, Clin. Infect. Dis.
  2. 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

Authors
Schultze, J. L., & Aschenbrenner, A. C.
Affiliations
University of Bonn (DE)
Corresponding author
Schultze, Joachim L.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-04
Volume
184
Issue
7
Pages
1671-1692
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.02.029
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
Licence
Locations
  • Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion)
Funders
Rheinische Friedrich-Wilhelms-Universität Bonn
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
COVID-19 pandemic, SARS-CoV-2, innate immunity, disease heterogeneity, soluble immune mediators, pathophysiology, diagnostic biomarkers, treatment options, host-virus interaction
MeSH terms
Host Microbial Interactions, COVID-19, SARS-CoV-2, Humans, Immunity, Innate, Severity of Illness Index

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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