Innate immunity and interferon in SARS-CoV-2 infection outcome

Savan, Ram; Gale, Michael

doi:10.1016/j.immuni.2023.06.018

Cited by 14 publications

(8 citation statements)

References 87 publications

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“…Then, the IFN score declined naturally as in other viral infections. It is now documented that the interferon response and score are only activated during the very early phase of viral infection and will largely be subsided at the end of the first week ( 55 , 56 , 59 ).Therefore our data further confirmed the importance of the timeframe for sample collection and examination of IFN genes Similarly, contradictory results of treatment with various exogenous interferon in different trials could be due to difference in the outcome measures and timing of the interferon administration. Whether interferon is administered early (within the first few days after onset) or late may result in completely different outcomes.…”

Section: Discussionsupporting

confidence: 78%

“…However, the ability of the virion to antagonist interferon pathway was only observed in specific in-vitro experiments and the ability of viral proteins to inhibit IFN responses differed among studies ( 55 ). It is not sure to what extent the inhibitory effects were due to overexpression of the viral protein in ectopic subcellular locations ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

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Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients

Huang,

Chiang

et al. 2024

Front. Immunol.

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IntroductionThere is insufficient understanding on systemic interferon (IFN) responses during COVID-19 infection. Early reports indicated that interferon responses were suppressed by the coronavirus (SARS-CoV-2) and clinical trials of administration of various kinds of interferons had been disappointing. Expression of interferon-stimulated genes (ISGs) in peripheral blood (better known as interferon score) has been a well-established bioassay marker of systemic IFN responses in autoimmune diseases. Therefore, with archival samples of a cohort of COVID-19 patients collected before the availability of vaccination, we aimed to better understand this innate immune response by studying the IFN score and related ISGs expression in bulk and single cell RNAs sequencing expression datasets.MethodsIn this study, we recruited 105 patients with COVID-19 and 30 healthy controls in Hong Kong. Clinical risk factors, disease course, and blood sampling times were recovered. Based on a set of five commonly used ISGs (IFIT1, IFIT2, IFI27, SIGLEC1, IFI44L), the IFN score was determined in blood leukocytes collected within 10 days after onset. The analysis was confined to those blood samples collected within 10 days after disease onset. Additional public datasets of bulk gene and single cell RNA sequencing of blood samples were used for the validation of IFN score results.ResultsCompared to the healthy controls, we showed that ISGs expression and IFN score were significantly increased during the first 10 days after COVID infection in majority of patients (71%). Among those low IFN responders, they were more commonly asymptomatic patients (71% vs 25%). 22 patients did not mount an overall significant IFN response and were classified as low IFN responders (IFN score < 1). However, early IFN score or ISGs level was not a prognostic biomarker and could not predict subsequent disease severity. Both IFI27 and SIGLEC1 were monocyte-predominant expressing ISGs and IFI27 were activated even among those low IFN responders as defined by IFN score. In conclusion, a substantial IFN response was documented in this cohort of COVID-19 patients who experience a natural infection before the vaccination era. Like innate immunity towards other virus, the ISGs activation was observed largely during the early course of infection (before day 10). Single-cell RNA sequencing data suggested monocytes were the cell-type that primarily accounted for the activation of two highly responsive ISGs (IFI44L and IFI27).DiscussionAs sampling time and age were two major confounders of ISG expression, they may account for contradicting observations among previous studies. On the other hand, the IFN score was not associated with the severity of the disease.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients

Huang,

Chiang

et al. 2024

Front. Immunol.

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“…Pulmonary delivery of the STING agonist 2'3' cGAMP 112 , the TLR3/MDA5 agonist Poly (I:C) 113 or the RIG-I agonist SLR14 114 were also shown to effectively reduce lung viral SCV2 burden when given prophylactically. In addition, IFN-I and IFN-III dependent control of viral replication in lung ECs has been shown to affect disease trajectories prior to the onset of T cell-mediated control 8,15,103,115 . In fact, SCV2 replication levels are associated with the likelihood of viral transmission, and the ability of children to mount a more robust protective innate immune response compared to adults correlates with reduced viral replication in ECs 5,6,[116][117][118][119] .…”

Section: Discussionmentioning

confidence: 99%

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

Baker,

Bohrer,

Castro

et al. 2024

Preprint

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SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. We demonstrate here that immune events in the mouse lung closely preceding SARS-CoV-2 infection significantly impact viral control and we identify key innate immune pathways required to limit viral replication. A diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections with S. aureus or influenza, ongoing pulmonary M. tuberculosis infection, ovalbumin/alum-induced asthma or airway administration of defined TLR ligands and recombinant cytokines, all establish an antiviral state in the lung that restricts SARS-CoV-2 replication upon infection. In addition to antiviral type I interferons, the broadly inducible inflammatory cytokines TNFα and IL-1 precondition the lung for enhanced viral control. Collectively, our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation that precedes or accompanies SARS-CoV-2 exposure may be a significant factor contributing to the population-wide variability in COVID-19 disease outcomes.

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“…Several PLSCR1 variants were enriched in a GWAS on severe COVID-19, with a relatively low odds ratio of approximately 1.2 [23, 24]. Considering the complex redundancies within antiviral defenses, from innate immunity featuring multiple effector ISGs that restrict SARS-CoV-2 [9–14, 17, 18], to adaptive immunity [154], the modest odds ratio associated with a single effector ISG not involved in IFN signaling may not be unexpected. However, for these very reasons, the identification of PLSCR1 in the GWAS remains noteworthy.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist

Le Pen,

Paniccia,

Kinast

et al. 2024

Preprint

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Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence SARS-CoV-2 infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of COVID-19 patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 over-expression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Our study contributes to understanding the association between PLSCR1 variants and severe COVID-19 cases reported in a recent GWAS.

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Innate immunity and interferon in SARS-CoV-2 infection outcome

Cited by 14 publications

References 87 publications

Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients

Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist

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