Dual Nature of Type I Interferons in SARS-CoV-2-Induced Inflammation

King, Charles M.; Sprent, Jonathan

doi:10.1016/j.it.2021.02.003

Cited by 98 publications

(111 citation statements)

References 107 publications

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“…Moreover, interfering with type I IFN signaling can redirect immunity to enable control of viral infection ( 41 ). In fact, the dual nature of type I IFNs in SARS-CoV-2induced inflammation has recently been elegantly reviewed by others ( 42 ). The observation that these drugs also reduced syncytia formation are intriguing since they suggest that complement may also influences the biology of the virus in cells CD46, the receptor for C3b, the other major product of C3 processing, is known to enhance syncytia formation in other viral infections ( 43 ), so it is possible that reducing active C3 also reduces syncytia formation.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

et al. 2021

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Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-κB as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-κB-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-κB-signaling could potentially have clinical application for severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

et al. 2021

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“…They found that IFN-I treatment is associated with positive clinical outcomes regarding mortality and discharge (56). The time to start IFN-I treatment might be crucial (57).…”

Section: Introductionmentioning

confidence: 99%

“…Disagreements related to the role of IFN-I in patients with COVID-19 demonstrate the importance of further studying these cytokines in the disease. The importance of IFN-I in the pathogenesis of the COVID-19 had been previously reviewed (30,(57)(58)(59)(60)(61). Nonetheless, the available evidence regarding the circulating levels of IFN-I and its response and the association with the severity of the disease has not been meta-analyzed.…”

Section: Introductionmentioning

confidence: 99%

Circulating Type I Interferon Levels and COVID-19 Severity: A Systematic Review and Meta-Analysis

et al. 2021

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IntroductionCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, resulting in a range of clinical manifestations and outcomes. Laboratory and immunological alterations have been considered as potential markers of disease severity and clinical evolution. Type I interferons (IFN-I), mainly represented by IFN-α and β, are a group of cytokines with an important function in antiviral responses and have played a complex role in COVID-19. Some studies have demonstrated that IFN-I levels and interferon response is elevated in mild cases, while other studies have noted this in severe cases. The involvement of IFN-I on the pathogenesis and outcomes of SARS-CoV-2 infection remains unclear. In this study, we summarize the available evidence of the association of plasma protein levels of type I IFN with the severity of COVID-19.MethodsThe PRISMA checklist guided the reporting of the data. A systematic search of the MEDLINE (PubMed), EMBASE, and Web of Science databases was performed up to March of 2021, looking for articles that evaluated plasma protein levels of IFN-I in mild, severe, or critical COVID-19 patients. Comparative meta-analyses with random effects were performed to compare the standardized mean differences in plasma protein levels of IFN-I of mild versus severe and mild versus critical patients. Meta-regressions were performed to test the moderating role of age, sex, time that the IFN-I was measured, and limit of detection of the assay used in the difference between the means.ResultsThere was no significant difference in plasma levels of IFN-α when comparing between mild and severe patients (SMD = -0.236, 95% CI -0.645 to 0.173, p = 0.258, I2 = 82.11), nor when comparing between patients mild and critical (SMD = 0.203, 95% CI -0.363 to 0.770, p = 0.481, I2 = 64.06). However, there was a significant difference between healthy individuals and patients with mild disease (SMD = 0.447, 95% CI 0.085 to 0.810, p = 0.016, I2 = 62.89).ConclusionsPeripheral IFN-α cannot be used as a severity marker as it does not determine the clinical status presented by COVID-19 patients.

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“…elsewhere (3,4). In brief, IFN-I comprises a mixture of IFNβ, multiple subtypes of IFN-α, and several other IFNs.…”

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confidence: 99%