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Type III interferons disrupt the lung epithelial barrier upon viral recognition

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Science  07 Aug 2020:
Vol. 369, Issue 6504, pp. 706-712
DOI: 10.1126/science.abc3545

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  • Response to: Interferon Lambda remains a strong candidate for the treatment of mild-to-moderate COVID-19.
    • Ivan Zanoni, Assistant Professor, Harvard Medical School - Boston Children's Hospital

    Interferon (IFN)-λ is a potent antiviral with limited tissue damage potential and is currently investigated as a therapeutic against SARS-CoV-2. We demonstrated IFN-λ impairs the lung barrier, facilitating secondary bacterial infections (1). Our findings give a potent mandate to rethink the pathophysiological role of IFN-λ and to hold off its use in the most severe COVID-19 cases, that often develop superinfections.

    The SARS-CoV-2 pandemic raised an unprecedented flux of studies aimed at unraveling the molecular mechanisms that determine the most severe cases of COVID-19 and at identifying new therapies to treat this disease. Among available therapeutic options, the use of clinical grade recombinant type I (IFN-α/β) or type III (IFN-λ) IFNs raised hope and interest. IFN-λ is particularly relevant, as it represents a gatekeeper of mucosal immunity (2, 3). IFN-λ is notable for its ability to induce an antiviral state while simultaneously limiting inflammation-driven tissue damage. The decreased tissue damage activity of IFN-λ compared to type I IFNs is mainly due to: i) the limited expression of the IFN-λ receptor (IFNLR) to epithelial cells and few other immune cell types (2); ii) the capacity of IFN-λ, compared to type I IFNs, to reduce chemokine production and inflammatory immune cell recruitment by epithelial cells (4); and iii) its capacity to decrease the tissue damaging functions of neutrophils (5). Furthermore, in mouse models of influenza A virus (IAV) infect...

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    Competing Interests: None declared.
  • Interferon Lambda remains a strong candidate for the treatment of mild-to-moderate COVID-19.
    • Thomas Marron, Physician Scientist, Assistant Director of Early Phase and Immunotherapy Trials, Icahn School of Medicine at Mount Sinai
    • Other Contributors:
      • Scott L. Friedman, Dean for Therapeutic Discovery, Icahn School of Medicine at Mount Sinai
      • Adolfo Garcia-Sastre, Director, Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai
      • Miriam Merad, Director, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai

    Interferons (IFNs) initiate both innate and adaptive immunity during viral infection. While Type I IFNs (IFN) bind to ubiquitously expressed receptors and induce significant inflammation, Type III interferons (IFN) are induced earlier in viral infection, bind to a receptor restricted primarily to the epithelium, and exert similar but non-redundant antiviral effect without the profound, potentially damaging inflammatory response[1]. The critical role that IFNs play in preventing viral infection is best illustrated by the presence of virus-encoded IFN antagonists in every pathogenic virus[2]. To block the induction of IFNs in infected cells, betacoronaviruses such as SARS-CoV-2 have several proteins capable of suppressing IFN and IFN production[3], the antiviral signaling of IFNs [4], and the antiviral activity of IFN-induced genes[5, 6]. Moreover, ex vivo infection of human lung tissue confirms SARS-CoV-2 induces particularly low levels of IFN even compared to SARS-CoV-1[7]. Preclinical work has shown a potent suppression of IFN by SARS-CoV-2 infected type II pneumocytes, which we hypothesize establishes a permissive milieu for unchecked viral replication[8]. The essential role that IFN antagonists have in licensing virus replication in vivo strongly suggests that exogenous treatment with IFNs, especially early in the course of infection, might result in curtailing viral infection and subsequent disease. While Type I IFNs are able to induce a potent antiviral re...

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    Competing Interests: As noted in our commentary, Dr. Marron is the Principle Investigator of a clinical trial investigating pegylated interferon lambda in mild to moderate COVID-19.

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