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Respiratory Syncytial Virus Protects Bystander Cells against Influenza A Virus Infection by Triggering Secretion of Type I and Type III Interferons
10.1128/jvi.01341-22
Maciej Czerkies
Marek Kochańczyk
Zbigniew Korwek
Wiktor Prus
Tomasz Lipniacki
Cellular Response to Infection
Cellular Response to Infection
influenza A virus
innate immunity
interferon beta
interferon lambda
respiratory syncytial virus
single cell
viral interference
American Society for Microbiology
Czerkies et al.
Copyright © 2022 Czerkies et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
20221103
2022
ABSTRACT
We observed the interference between two prevalent respiratory viruses, respiratory syncytial virus (RSV) and influenza A virus (IAV) (H1N1), and characterized its molecular underpinnings in alveolar epithelial cells (A549). We found that RSV induces higher levels of interferon beta (IFN-β) production than IAV and that IFN-β priming confers higher-level protection against infection with IAV than with RSV. Consequently, we focused on the sequential infection scheme of RSV and then IAV. Using A549 wild-type (WT), IFNAR1 knockout (KO), IFNLR1 KO, and IFNAR1-IFNLR1 double-KO cell lines, we found that both IFN-β and IFN-λ are necessary for maximum protection against subsequent infection. Immunostaining revealed that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. Strikingly, the susceptible cells turned out to be those already compromised and efficiently expressing RSV, whereas the bystander, interferon-primed cells are resistant to IAV infection. Thus, virus-virus exclusion at the cell population level is not realized through direct competition for a shared ecological niche (single cell) but rather is achieved with the involvement of specific cytokines induced by the host’s innate immune response.
IMPORTANCE Influenza A virus (IAV) and respiratory syncytial virus (RSV) are common recurrent respiratory infectants that show a relatively high coincidence. We demonstrated that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. The susceptible cells are those already compromised and efficiently expressing RSV, whereas the bystander cells are resistant to IAV infection. The cross-protective effect critically depends on IFN-β and IFN-λ signaling and thus ensues when the proportion of cells preinfected with RSV is relatively low yet sufficient to trigger a pervasive antiviral state in bystander cells. Our study suggests that mild, but not severe, respiratory infections may have a short-lasting protective role against more dangerous respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
20220827
20221008
1098-5514
Adobe LiveCycle PDF Generator; modified using iText® 5.5.13.2 ©2000-2020 iText Group NV (AGPL-version)2022-11-25T03:30:54-08:00
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