Increased Sensitivity of SARS-CoV-2 to Type III Interferon in Human Intestinal Epithelial Cells

Metz-Zumaran, Camila; Kee, Carmon; Doldan, Patricio; Guo, Cheng; Stanifer, Megan L.; Boulant, Steeve

doi:10.1128/jvi.01705-21

Cited by 19 publications

(14 citation statements)

References 79 publications

(115 reference statements)

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“…Many ISGs downregulate antiviral responses through a negative feedback mechanism ( 7 , 10 , 11 , 41 ), as exacerbated innate immune responses can be deleterious for the host. Taking this information into account, and the fact that IAV and SARS-CoV-2 are unrelated viruses which are sensitive to IFN responses ( 42 , 43 ), we hypothesized that IFI6 could be modulating the induction of the host antiviral responses. To test this hypothesis and to get a broader insight on the effect of IFI6 on host responses, the transcriptomes of human leukemia-derived HAP-1 control cells and IFI6 KO cells were compared by RNAseq.…”

Section: Resultsmentioning

confidence: 99%

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

et al. 2023

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Interferons (IFNs), IFN-stimulated genes (ISGs), and inflammatory cytokines mediate innate immune responses, and are essential to establish an antiviral response. Within the innate immune responses, retinoic acid-inducible gene I (RIG-I) is a key sensor of virus infections, mediating the transcriptional induction of IFNs and inflammatory proteins. Nevertheless, since excessive responses could be detrimental to the host, these responses need to be tightly regulated. In this work, we describe, for the first time, how knocking-down or knocking-out the expression of IFN alpha-inducible protein 6 (IFI6) increases IFN, ISG, and pro-inflammatory cytokine expression after the infections with Influenza A Virus (IAV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Sendai Virus (SeV), or poly(I:C) transfection. We also show how overexpression of IFI6 produces the opposite effect, in vitro and in vivo, indicating that IFI6 negatively modulates the induction of innate immune responses. Knocking-out or knocking-down the expression of IFI6 diminishes the production of infectious IAV and SARS-CoV-2, most likely because of its effect on antiviral responses. Importantly, we report a novel interaction of IFI6 with RIG-I, most likely mediated through binding to RNA, that affects RIG-I activation, providing a molecular mechanism for the effect of IFI6 on negatively regulating innate immunity. Remarkably, these new functions of IFI6 could be targeted to treat diseases associated with an exacerbated induction of innate immune responses and to combat viral infections, such as IAV and SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

et al. 2023

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“…SARS-CoV-2 proteins impair MDA5/RIG-I and TLR3-TRIF signaling, leading to suppression of type III IFNs [ 34 , 38 ]. At the same time, several in vitro studies have shown strong antiviral effects of type III IFNs against SARS-CoV-2 replication [ 39 , 40 ]. Furthermore, Sohn et al recently showed that intranasal treatment with IFNλ decreased immunopathogenesis associated with SARS-CoV-2 in transgenic mice expressing angiotensin-converting enzyme II (ACE-II) [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Expression of IFN Lambda, IFN Gamma and Toll-like Receptors in Severe COVID-19 Patients

et al. 2023

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Contradictory results have been reported regarding interferon (IFN) lambda (λ1–3) and IFN gamma (γ) production in COVID-19 patients. To gain insight into the roles played by these IFNs in SARS-CoV-2 infection, IFNλ1–3 and IFNγ mRNA expression was evaluated in peripheral blood mononuclear cells (PBMCs) (n = 32) and in cells of paired bronchoalveolar lavages (BALs) (n = 12). Lower IFNλ1–3 values (p < 0.001 for IFNλ1 and 3 and p = 0.013 for IFNλ2) in the PBMCs of severely ill patients were found compared to healthy donors (n = 15). Reduced levels of IFNγ were also detected in patients’ PBMCs (p < 0.01) and BALs (p = 0.041) compared to healthy donors. The presence of secondary bacterial infections was associated with decreased IFNλ amounts in PBMCs (p = 0.001, p = 0.015 and p = 0.003, respectively) but increased concentrations of IFNλ3 (p = 0.022) in BALs. Patients with alterations in C-reactive protein, lactate dehydrogenase and D-dimer levels had decreased IFNλ1 and 3 (p = 0.003 and p < 0.001) and increased IFNγ (p = 0.08) in PBMCs. Analyzing Toll-like receptors (TLRs) involved in IFN production, we found that TLR3 was highly expressed (p = 0.033) in patients with bacterial superinfections, while TLR7 and 8 (p = 0.029 and p = 0.049) were reduced in BALs of deceased patients. Overall, severe COVID-19 might be characterized by dysregulation in IFNγ, IFNλ and TLR3, 7 and 8 production.

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“…After pretreatment of human intestinal cell lines with IFN-β and human colon organoids with IFN-β1 and type III IFN, respectively, a protective effect against SARS-CoV-2 infection was observed, resulting in a significantly milder infection ( 43 , 44 ). However, the antiviral activity of type III IFN against SARS-CoV-2 in the gut is stronger and more durable ( 45 ). Of note, infection of colon organoids with SARS-CoV-2 resulted in upregulation of type III IFN but not type I IFN, despite the ability of these organoids to produce both types in response to viral infection ( 44 , 46 ).…”

Section: Sars-cov-2-mediated Changes In the Intestinal Immunological ...mentioning

confidence: 99%

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential

et al. 2023

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Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.

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Increased Sensitivity of SARS-CoV-2 to Type III Interferon in Human Intestinal Epithelial Cells

Abstract: SARS-CoV-2 infection is not restricted to the respiratory tract and a large number of COVID-19 patients experience gastrointestinal distress. Interferons are key molecules produced by the cell to combat virus infection.

Cited by 19 publications

References 79 publications

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

Alterations in the Expression of IFN Lambda, IFN Gamma and Toll-like Receptors in Severe COVID-19 Patients

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential

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