Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities

Alline Da Rocha Matos ,Katharina Wunderlich,Sebastian Schloer,Klaus Schughart,Robert Geffers,Martine Seders,Marlous De Witt,Anmari Christersson,Rainer Wiewrodt,Karsten Wiebe,Peter Barth,Stefan Hippenstiel,Katja Hönzke,Ulf Dittmer,Kathrin Sutter,Ursula Rescher,Svetlana Rodionycheva,Andreas C Hocke ,Nicoletta Matera,Stephan Ludwig,Linda Brunotte

doi:10.1080/22221751.2019.1698271

Abstract

ABSTRACT Influenza is an acute respiratory infection causing high morbidity and mortality in annual outbreaks worldwide. Antiviral drugs are limited and pose the risk of resistance development, calling for new treatment options. IFN-α subtypes are immune-stimulatory cytokines with strong antiviral activities against IAV in vitro and in vivo. However, the clinical use of IFN-α2, the only licensed subtype of this multi-gene family, could not prevent or limit IAV infections in humans. However, the other subtypes were not investigated. Therefore, this study evaluated the induction and antiviral potential of all human IFN-α subtypes during H3N2 IAV infection in human lung explants. We found that subtypes with weak antiviral activities were preferentially induced during IAV infection in human lungs. Intriguingly, non-induced subtypes α16, α5 and α4 suppressed viral replication up to 230-fold more efficiently than α2. Furthermore, our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV. These results corroborate that IFN-α subtypes exhibit differential antiviral activities and emphasize that subtypes α16, α5 and α4 should be further investigated for the prevention and treatment of severe infections with seasonal H3N2 IAV.

Highlights

Influenza A viruses (IAV) cause recurring, highly infectious respiratory disease with mild to severe symptoms
Our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV
These results demonstrate that human lung explants support IAV replication and reinforce that lung explants provide a suitable model to study pathogen host interactions of respiratory viruses in primary human lung tissue [41]

Summary

Introduction

Influenza A viruses (IAV) cause recurring, highly infectious respiratory disease with mild to severe symptoms. Circulating IAV strains include the 2009 pandemic H1N1 strain (H1N1pdm09) as well as H3N2 strains [3]. Prevention of IAV infection can be achieved by annual vaccination and is of particular importance to elderly, infants, pregnant women and immune-compromised individuals, which are at high risk to develop severe symptoms. Sporadic low efficacy of vaccines, due to mismatches between the circulating viruses and vaccine strains, and increasing scepticism towards the risks and benefits of vaccination raise the need for therapeutic treatments [4,5,6]. Introduction of new IAV strains with pandemic potential from animal reservoirs into the human population, for which a vaccine could not be timely available, remains to be a threat

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