IRF7 Is Required for the Second Phase Interferon Induction during Influenza Virus Infection in Human Lung Epithelia.

Wenxin Wu,Wei Zhang,Lili Tian,Matthew S Walters,Brent R Brown,Jordan P Metcalf

doi:10.3390/v12040377

Wenxin Wu, Wei Zhang + Show 4 more

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https://doi.org/10.3390/v12040377

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Abstract

Influenza A virus (IAV) infection is a major cause of morbidity and mortality. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of IAV in most cell types, and leads to the activation of interferon (IFN). We investigated mechanisms of RIG-I and IFN induction by IAV in the BCi-NS1.1 immortalized human airway basal cell line and in the A549 human alveolar epithelial cell line. We found that the basal expression levels of RIG-I and regulatory transcription factor (IRF) 7 were very low in BCi-NS1.1 cells. IAV infection induced robust RIG-I and IRF7, not IRF3, expression. siRNA against IRF7 and mitochondrial antiviral-signaling protein (MAVS), but not IRF3, significantly inhibited RIG-I mRNA expression and IFN induction by IAV infection. Most importantly, even without virus infection, IFN-β alone induced RIG-I, and siRNA against IRF7 did not inhibit RIG-I induction by IFN-β. Similar results were found in the alveolar basal epithelial A549 cell line. RIG-I and IRF7 expression in humans is highly inducible and greatly amplified by IFN produced from virus infected cells. IFN induction can be separated into two phases, that initially induced by the virus with basal RIG-I (the first phase), and that induced by the subsequent virus with amplified RIG-I from the first phase IFN (the second phase). The de novo synthesis of IRF7 is required for the second phase IFN induction during influenza virus infection in human lung bronchial and alveolar epithelial cells.

Highlights

Influenza A virus (IAV) infection is a major cause of morbidity and mortality
We have previously shown that both RIG-I and Toll-like receptor 3 (TLR3) are important for IFN induction by IAV in human lung alveolar epithelial cells (AEC) [3]
We extended our work to more distal epithelial cells in the lung, human alveolar epithelial cells

Summary

Introduction

Influenza A virus (IAV) infection is a major cause of morbidity and mortality. In 2009, a pandemic caused by the novel H1N1 IAV infected over 300,000 individuals with at least 16,000 confirmed deaths worldwide [1]. It is estimated that the burden of illness during the 2017–2018 season was high with an estimated 45 million people getting sick with influenza, 21 million people going to a health care provider, 810,000 hospitalizations, and 61,000 deaths from influenza (from 2017–2018 Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths and Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths Averted by Vaccination in the United States, Centers for Disease Control and Prevention). The innate immune system recognizes and responds to pathogens in a non-specific manner and provides immediate protection against infection.

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