Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Major, Jack; Crotta, Stefania; Llorian, Miriam; McCabe, Teresa M; Gad, Hans Henrik; Priestnall, Simon L.; Hartmann, Rune; Wack, Andreas

doi:10.1126/science.abc2061

Cited by 356 publications

(288 citation statements)

References 38 publications

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“…For cycloheximide experiments, cells were treated with 250 µg ml −1 cycloheximide (Sigma-Aldrich) and harvested at denoted time points. NHBE cells were stimulated for 4 h with 1,000 ng ml −1 IFN-α, 100 ng ml −1 IFN-β or 100 ng ml −1 IFN-λ, as used in a previous study 22 , and stored cDNA was analyzed by RT-qPCR in this study.…”

Section: Methodsmentioning

confidence: 99%

Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

Attig

Bolland

et al. 2020

Nat Genet

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Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a regulator of several physiological processes. ACE2 has recently been proposed to be interferon (IFN) inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of IFN treatment in coronavirus disease 2019. Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a new isoform of ACE2, generated by co-option of intronic retroelements as promoter and alternative exon. The new transcript, termed MIRb-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and is highly responsive to IFN stimulation. In contrast, canonical ACE2 expression is unresponsive to IFN stimulation. Moreover, the MIRb-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and is therefore unlikely to contribute to or enhance viral infection. NATuRE GENETiCS | www.nature.com/naturegenetics Articles NATURE GENETICS which indicated peaks in the LTR16A1 retroelement and the immediately upstream MIRb retroelement in the same intronic region (Extended Data Fig. 1). FANTOM5 CAGE peak distribution over the LTR16A1 and MIRb retroelements exhibited cell-type specificity to a certain degree, with peaks residing almost exclusively in MIRb in bronchial epithelial cells but extending to LTR16A1 in HEK293 cells (Extended Data Fig. 1). Both LTR16A1 and MIRb retroelements contained multiple transcription factor binding sites, with IRF-1 and IRF-2 binding sites and TATA-box residing in MIRb (Extended Data Fig. 2). To further define the transcription start site(s), we performed 5′ rapid amplification of cDNA ends (RACE) PCR, followed by deep sequencing of the PCR products, amplified from normal human bronchial epithelial (NHBE) cells or human squamous cell carcinoma (SCC) cell lines SCC-4 and SCC-25, treated with recombinant IFN-α (Extended Data Fig. 2). Consistent with FANTOM5 CAGE data, 5′ RACE analysis showed multiple peaks in both LTR16A1 and MIRb, again with evidence of celltype specificity in their relative utilization (Extended Data Fig. 2).

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Section: Methodsmentioning

confidence: 99%

Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

Attig

Bolland

et al. 2020

Nat Genet

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“…Interestingly, IFN-λ is present in lower airways in COVID-19 patients where it mediates antiproliferative effects in during the repair of the lung epithelium. This antiprolifertative effect occurs via p53 induction, but due to its slowing of epithelial repair, may increase the risk of life-threating bacterial superinfections in the lung during both influenza and COVID-19 infection (46,47). Thus, timing and duration are critical parameters of IFN action and in COVID-19 patients who contract a secondary bacterial infection, it might be crucial to intervene with recombinant interferons when virus is in upper airways.…”

Section: Interferons and Cytokinesmentioning

confidence: 99%

Covid-19: Perspectives on Innate Immune Evasion

et al. 2020

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The ongoing outbreak of Coronavirus disease 2019 infection achieved pandemic status on March 11, 2020. As of September 8, 2020 it has caused over 890,000 mortalities worldwide. Coronaviral infections are enabled by potent immunoevasory mechanisms that target multiple aspects of innate immunity, with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) able to induce a cytokine storm, impair interferon responses, and suppress antigen presentation on both MHC class I and class II. Understanding the immune responses to SARS-CoV-2 and its immunoevasion approaches will improve our understanding of pathogenesis, virus clearance, and contribute toward vaccine and immunotherepeutic design and evaluation. This review discusses the known host innate immune response and immune evasion mechanisms driving SARS-CoV-2 infection and pathophysiology.

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“…Another, important parameter is the time of intervention by IFN-I, in early or late-stage COVID-19 disease. In a recent study in mice it has been shown that prolonged IFN-I and III signaling interferes with lung repair during influenza recovery, probably through p53 induction, which reduces epithelial proliferation and healing, while early treatment protects mice (119). In SARS-CoV-2 this is further complicated by the "cytokine-storm" symptoms of severe COVID-19, as indicated by elevated IL6 and TNF-alpha levels.…”

Section: Treating Covid-19 Patients With Ifn-imentioning

confidence: 99%

The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

2020

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Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNb and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I-receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.

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Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Cited by 356 publications

References 38 publications

Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

Covid-19: Perspectives on Innate Immune Evasion

The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

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