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

I 型和 III 型干扰素在塑造甲型流感病毒宿主内部和之间动态中的作用

• 批准号: 10681893
• 负责人: Anice C Lowen
• 金额: $ 24.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681893
• 关键词: Ablation; Address; Aerosols; Affect; Antiviral Response; Bar Codes; Biological; CRISPR/Cas technology; Cavia; Cells; Environmental Risk Factor; Epithelium; Evolution; Genetic; Genetic Drift; Genetic Structures; Genetic Variation; Genome; Health; IFNAR1 gene; Individual; Infection; Influenza A Virus, H3N2 Subtype; Influenza A virus; Integration Host Factors; Interferon Type I; Interferon alpha; Interferon-beta; Interferons; Kinetics; Knock-out; Lead; Modeling; Molecular; Monitor; Mus; Natural Selections; Panama; Population; Population Dynamics; Population Genetics; Population Sizes; Positioning Attribute; Predisposition; Process; Property; Proteins; Public Health; RNA Viruses; Research; Role; Route; Seasons; Shapes; Signal Transduction; Site; Spatial Distribution; Testing; Variant; Viral; Viral Load result; Virus; Work; airway epithelium; cytokine; deep sequencing; design; economic impact; fitness; flu transmission; influenza epidemic; influenza virus strain; influenzavirus; pandemic disease; particle; receptor; response; reverse genetics; seasonal influenza; tool; transmission process; type I interferon receptor; viral transmission; virus genetics

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.

概括 几十年来，人们已经认识到干扰素 (IFN) 细胞因子在先天抗病毒反应中的核心作用 其诱导及其引发的反应的许多机制已在 然而，人们对 IFN 对病毒遗传结构的影响却知之甚少。 我们勇敢地面对干扰素对病毒传播的限制。 减少了受感染宿主内病毒种群的有效规模，并导致了感染过程中的严重瓶颈 由于它们的不同特性，我们进一步期望 I 型的不同效果。 IFN 和 III 型 IFN (IFN-λ) 预计两者都会限制受感染宿主内的多样性，但可能会这样做。 此外，由于其在上皮细胞内的局部作用，我们预计 IFN-λ 具有不同的动力学。 有助于进一步减少宿主之间传播期间的有效群体规模。 假设我们将利用两个有价值的实验工具。第一个是 CRISPR 的应用。 Cas-9 编辑产生缺乏 IFNAR1 或 IFNLR1（I 型 IFN 和 IFN-受体）的豚鼠 豚鼠天然易感染多种甲型流感病毒 (IAV) 和流感病毒。 跟踪宿主内感染的纵向动态以及传播到新宿主的优秀模型 第二个工具是携带高度多样化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对病毒动态的影响 通过宿主和病毒遗传学的结合，我们有能力揭示干扰素信号传导。 I 型 IFN 和 IFN-λ（哺乳动物先天防御的关键）对病毒遗传多样性和 进化潜力。