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

总结 干扰素（IFN）细胞因子在先天性抗病毒反应中的核心作用已被认识了几十年 许多诱导和引发反应的机制已经在 分子细节然而，IFN对病毒基因结构的影响却不太清楚。 宿主内和宿主间的种群。我们假设干扰素对病毒繁殖的限制 减少了受感染宿主内病毒群体的有效大小， 传播到新的宿主。由于它们的不同性质，我们进一步预期I型的不同效果。 IFN和III型IFN（IFN-λ）。我们预计，这两种病毒都会限制受感染宿主内的多样性， 不同的动力学。此外，由于其在上皮内的局部作用，我们预计IFN-λ 有助于在宿主之间传播期间进一步减少有效种群大小。测试这些 假设我们将利用两种有价值的实验工具。首先是CRISPR的应用 Cas-9编辑以产生缺乏IFNAR 1或IFNLR 1的豚鼠，IFNAR 1或IFNLR 1是I型IFN和IFN-γ的受体。 λ，分别。豚鼠自然易感染多种甲型流感病毒（IAV）， 这是跟踪宿主内感染的纵向动态以及向新宿主传播的极好模型。 hosts.第二个工具是携带高度多样性和适应性中性遗传条形码的IAV群体。 通过深度测序监测条形码多样性将使我们能够确定 干扰IFN信号传导。有了这种宿主和病毒遗传学的结合，我们处于有利地位，可以揭示 I型IFN和IFN-λ是哺乳动物先天防御的关键，对病毒遗传多样性的影响， 进化潜力

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.