Abstract
Homotypic co-infections with influenza viruses are described to increase genetic population diversity, to drive viral evolution and to allow genetic complementation. Less is known about heterotypic co-infections between influenza A (IAV) and influenza B (IBV) viruses. Previous publications showed that IAV replication was suppressed upon co-infection with IBV. However, the effect of heterotypic co-infections on IBV replication was not investigated. To do so, we produced by reverse genetics a pair of replication-competent recombinant IAV (A/WSN/33) and IBV (B/Brisbane/60/2008) expressing a GFP and mCherry fluorescent reporter, respectively. A549 cells were infected simultaneously or 1 h apart at a high MOI with IAV-GFP or IBV-mCherry and the fluorescence was measured at 6 h post-infection by flow cytometry. Unexpectedly, we observed that IBV-mCherry infection was enhanced upon co-infection with IAV-GFP, and more strongly so when IAV was added 1 h prior to IBV. The same effect was observed with wild-type viruses and with various strains of IAV. Using UV-inactivated IAV or type-specific antiviral compounds, we showed that the enhancing effect of IAV infection on IBV infection was dependent on transcription/replication of the IAV genome. Our results, taken with available data in the literature, support the hypothesis that the presence of IAV proteins can enhance IBV genome expression and/or complement IBV defective particles.
Highlights
Influenza A (IAV) and influenza B viruses (IBV) are responsible for seasonal epidemics that cause significant mortality and morbidity in humans each year
We further showed that UV-inactivation or inhibition of IAV transcription/replication with specific drugs abolished the capacity of IAV co-infection to enhance IBV infection
We developed an original and efficient system to investigate the effects of heterotypic co-infections between IAV and IBV using fluorescent reporter viruses of both viral types
Summary
Influenza A (IAV) and influenza B viruses (IBV) are responsible for seasonal epidemics that cause significant mortality and morbidity in humans each year. In 2017, the frequency of heterotypic co-infections reached 1.3% and was associated with a high frequency of A(H3N2) and IBV co-circulation, increasing the chance of co-infection (Gregianini et al, 2019) In this context, the clinical significance of mixed influenza virus infection is not well understood, and its relation to the disease severity is unclear. Several reports have indicated that, upon co-infection of cells in vitro, IBV impairs the replication of IAV, a phenomenon called intertypic or heterotypic interference (Tobita and Ohori, 1979; Mikheeva and Ghendon, 1982; Kaverin et al, 1983; Aoki et al, 1984). We further showed that UV-inactivation or inhibition of IAV transcription/replication with specific drugs abolished the capacity of IAV co-infection to enhance IBV infection
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