Role of Type I and III Interferons in Shaping Influenza A Virus Dynamics Within and Between Hosts

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Summary The central role of the interferon (IFN) cytokines in innate antiviral responses has been recognized for decades and many of the mechanisms underlying their induction and the responses they trigger have been worked out in molecular detail. Much less well-understood, however, is the impact of IFN on the genetic structure of viral populations within and between hosts. We hypothesize that the restriction of viral propagation imposed by IFNs reduces the effective size of viral populations within infected hosts and contributes to tight bottlenecks during transmission to new hosts. Owing to their different properties, we furthermore expect differing effects of type I IFN and type III IFN (IFN-λ). We anticipate that both will restrict diversity within an infected host, but may do so with differing kinetics. In addition, due to its localized action within the epithelium, we expect that IFN-λ contributes to a further reduction in effective population size during transmission between hosts. To test these hypotheses we will leverage two valuable experimental tools. The first constitutes the application of CRISPR Cas-9 editing to generate guinea pigs that lack either IFNAR1 or IFNLR1, the receptors for type I IFN and IFN- λ, respectively. Guinea pigs are naturally susceptible to a wide range of influenza A viruses (IAVs) and an excellent model for following the longitudinal dynamics of infection within a host as well as transmission to new hosts. The second tool is an IAV population carrying a highly diverse and fitness-neutral genetic barcode. Monitoring barcode diversity through deep sequencing will allow us to determine the impact on viral dynamics of disrupting IFN signaling. With this combination of host and viral genetics, we are well-positioned to uncover the effects of type I IFN and IFN-λ, the lynch-pins of mammalian innate defenses, on viral genetic diversity and evolutionary potential.