RESUMEN
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.
Asunto(s)
Enzima Convertidora de Angiotensina 2/biosíntesis , Interferones/metabolismo , Retroelementos/genética , Enzima Convertidora de Angiotensina 2/genética , Animales , Línea Celular , Chlorocebus aethiops , Inducción Enzimática , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Regulación Viral de la Expresión Génica , Células HEK293 , Humanos , Isoenzimas/biosíntesis , Isoenzimas/genética , Estabilidad Proteica , RNA-Seq , Receptores de Coronavirus/metabolismo , SARS-CoV-2/metabolismo , Distribución Tisular , Células VeroRESUMEN
Developing effective in vivo models for SARS-CoV-2 infection is crucial for mechanistic studies of COVID-19 disease progression. In this issue of JEM, Israelow et al. (https://doi.org/10.1084/jem.20201241) generate a model that supports SARS-CoV-2 infection in mice, which they use to characterize type I IFN-driven pulmonary inflammation.
Asunto(s)
Infecciones por Coronavirus , Interferón Tipo I , Pandemias , Neumonía Viral , Síndrome Respiratorio Agudo Grave , Animales , Betacoronavirus , COVID-19 , Ratones , SARS-CoV-2RESUMEN
Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-ß) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-ß responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).