COVID-19 and the human innate immune system

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).”

What the sources say

• Partly supported

  The Results section (page unavailable) reports functional tests showing that SARS-CoV-2 ORF3b suppresses IFN-I activation. It mentions ORF6 inhibition of IFN-I production as a finding of previous studies, but does not report functional tests of ORF6, NSP1, or NSP13, or the claimed effects of ORF6 on STAT1/STAT2 phosphorylation and STAT1 nuclear translocation. Its nuclear-translocation result concerns IRF3 in the presence of ORF3b. (LLM, conf=0.88)

  cites Konno et al., 2020 sourceExperimental — accuracy not yet measured
• Disputed

  In Results, “ORF6 inhibits STAT1 nuclear translocation via its C-terminus” (Fig. 6), the paper reports that ORF6 blocks STAT1 nuclear translocation but explicitly says IFN-induced STAT1 phosphorylation remains intact—the opposite of the claim. The Results also show that NSP1, NSP13, and ORF6 inhibit IFN-β-induced reporter activity, but the cited passages do not establish ORF6 suppression of STAT2 phosphorylation. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites Lei et al., 2020 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on IFN-I signaling reports antagonistic activity by nsp1, nsp13 and ORF6, and shows that ORF6 blocks STAT1 nuclear translocation. It tests ORF3a, not ORF3b. It also finds that ORF6 only marginally suppresses STAT1 and STAT2 phosphorylation, contrary to the claim that ORF6 particularly suppresses both. (LLM, conf=0.90)

  cites Xia et al., 2020 sourceExperimental — accuracy not yet measured

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).”

What the sources say

• Not checked yetcites RECOVERY Collaborative Group et al., 2021
• Disputed

  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.

  cites Tomazini et al., 2020 sourceExperimental — accuracy not yet measured
• Not checked yetcites WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020

In the paper

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

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)”

What the sources say

• Not checked yetcites Gupta et al., 2020 source

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.”

What the sources say

• Not checked yetcites Sungnak et al., 2020 source

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).”

What the sources say

• Not checked yetcites Morens and Fauci, 2020

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).”

What the sources say

• Not checked yetcites Yang et al., 2020a

In the paper

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

What the sources say

• Not checked yetcites Morens and Fauci, 2020

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.”

What the sources say

• Not checked yetcites Candido et al., 2020 source
• Not checked yetcites Oude Munnink et al., 2020 source

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.”

What the sources say

• Not checked yetcites Sungnak et al., 2020 source

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)”

What the sources say

• Not checked yetcites Han et al., 2020 source

In the paper

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

What the sources say

• Not checked yetcites Onabajo et al., 2020 source

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.”

What the sources say

• Not checked yetcites de Figueiredo et al., 2020 source
• Not checked yetcites Song et al., 2021 source

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).”

What the sources say

• Not checked yetcites Merad and Martin, 2020 source
• Not checked yetcites Vabret et al., 2020 source
• Not checked yetcites Marshall, 2020 source

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).”

What the sources say

• Not checked yetcites Ashary et al., 2020 source

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).”

What the sources say

• Not checked yetcites Zhang et al., 2020b

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).”

What the sources say

• Not checked yetcites Israelow et al., 2020 source

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).”

What the sources say

• Not checked yetcites Lucas et al., 2020 source

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.”

What the sources say

• Not checked yetcites Bost et al., 2020 source

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.”

What the sources say

• Not checked yetcites Zhang et al., 2020b

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).”

What the sources say

• Not checked yetcites Ashary et al., 2020 source

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).”

What the sources say

• Not checked yetcites Snijder et al., 2020 source

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”

What the sources say

• Not checked yetcites Banerjee et al., 2020 source
• Not checked yetcites Gordon et al., 2020 source

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.”

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”

What the sources say

• Not checked yetcites Cao, 2020 source
• Not checked yetcites Lucas et al., 2020 source
• Not checked yetcites Wang et al., 2020a

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”

What the sources say

• Not checked yetcites Gordon et al., 2020 source
• Not checked yetcites Xia et al., 2020 source

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”

What the sources say

• Not checked yetcites Mazaleuskaya et al., 2012 source
• Not checked yetcites Sa Ribero et al., 2020 source

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).”

What the sources say

• Not checked yetcites Blanco-Melo et al., 2020 source

In the paper

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

What the sources say

• Not checked yetcites Xiong et al., 2020 source
• Not checked yetcites Blanco-Melo et al., 2020 source
• Not checked yetcites Hadjadj et al., 2020 source

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”

What the sources say

• Not checked yetcites Loo and Gale, 2011

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).”

What the sources say

• Not checked yetcites Arunachalam et al., 2020 source

In the paper

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

What the sources say

• Not checked yetcites Loo and Gale, 2011

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).”

What the sources say

• Not checked yetcites Hadjadj et al., 2020 source

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).”

What the sources say

• Not checked yetcites Ackermann et al., 2020 source
• Not checked yetcites Gupta et al., 2020 source
• Not checked yetcites Zhang et al., 2020b

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”

What the sources say

• Not checked yetcites Talemi and Höfer, 2018
• Not checked yetcites Rand et al., 2012 source
• Not checked yetcites Wimmers et al., 2018 source

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).”

What the sources say

• Not checked yetcites Acharya et al., 2020 source
• Not checked yetcites Blanco-Melo et al., 2020 source
• Not checked yetcites Sa Ribero et al., 2020 source

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Zhang et al., 2020a
• Not checked yetcites Bastard et al., 2020 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Hadjadj et al., 2020; Wang et al., 2020b

In the paper

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

What the sources say

• Not checked yetcites Sette and Crotty, 2021 source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Shen et al., 2020 source

In the paper

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

What the sources say

• Not checked yetcites Riva et al., 2020 source

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.”

What the sources say

• Not checked yetcites Del Valle et al., 2020 source

In the paper

“suggested that host genetics might contribute to disease susceptibility and severity”

What the sources say

• Not checked yetcites Ovsyannikova et al., 2020 source

In the paper

“A specialized form of innate immune adaptation is the induction of immune memory (also termed 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

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”

What the sources say

• Not checked yetcites Franceschi et al., 2017 source
• Not checked yetcites Frasca and Blomberg, 2016

In the paper

“Mild COVID-19 patients were marked by circulating HLA-DR hi CD11c hi inflammatory monocytes with an interferon-stimulated gene signature”

What the sources say

• Not checked yetcites Schulte-Schrepping et al., 2020 source

In the paper

“suggesting the lung as a source for the elevated plasma levels of type I IFNs early on infection”

What the sources say

• Not checked yetcites Kuri-Cervantes et al., 2020 source
• Not checked yetcites Arunachalam et al., 2020 source
• Not checked yetcites Lucas et al., 2020 source

In the paper

“An increase in circulating neutrophils versus a decrease in lymphocytes has been appreciated as a hallmark of severe COVID-19”

What the sources say

• Not checked yetcites Hadjadj et al., 2020 source
• Not checked yetcites Mathew et al., 2020 source
• Not checked yetcites Qin et al., 2020 source

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).”

What the sources say

• Not checked yetcites Salisbury, 2020 source
• Not checked yetcites Taquet et al., 2021 source

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.”

What the sources say

• Not checked yetcites van de Veerdonk et al., 2020 source
• Not checked yetcites Mastellos et al., 2020 source

In the paper

“suppressed the production of proinflammatory cytokines in lung macrophages, and the recruitment of neutrophils to the lung (Hoang et al., 2021).”

What the sources say

• Not checked yetcites Hoang et al., 2021 source

In the paper

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

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).”

What the sources say

• Not checked yetcites Messner et al., 2020 source
• Not checked yetcites Su et al., 2020

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).”

What the sources say

• Not checked yetcites Marshall, 2020 source

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.”

What the sources say

• Not checked yetcites Anderson et al., 2020 source
• Not checked yetcites Polack et al., 2020 source

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.”

In the paper

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

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.”

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.”

In the paper

“Organ involvement, magnitude of clinical symptoms, and length of this phase is highly variable”