Impact of intra-host population structure on influenza virus antigenic evolution

宿主内群体结构对流感病毒抗原进化的影响

• 批准号: 10349407
• 负责人: Anice C Lowen
• 金额: $ 38.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349407
• 关键词: Acute; Address; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Bar Codes; Cavia; Color; Detection; Evaluation; Evolution; Genes; Genetic; Genetic Structures; Genetic Variation; Heterogeneity; Human; Immunity; Immunization Programs; Individual; Infection; Influenza A virus; Knowledge; Location; Modeling; Monitor; Mutation; Oranges; Outcome; Pattern; Play; Population; Population Genetics; Prevalence; Process; Public Health; Research; Role; Severities; Shapes; Single Nucleotide Polymorphism; Site; Structure; System; Testing; Tissues; Uncertainty; Vaccination; Variant; Viral; Viral Genome; Virus; Virus Diseases; design; economic impact; fitness; genetic linkage; in vivo; influenza epidemic; influenzavirus; insight; neutralizing antibody; next generation sequencing; novel; population genetic structure; pressure; response; reverse genetics; sample collection; seasonal influenza; transmission process; virus genetics

SUMMARY At the global population level, seasonal influenza A virus (IAV) evolution is characterized by repeated selective sweeps in which novel antigenic variants that escape antibody responses replace previously circulating strains. Despite this clear pattern at a population level, selection of antigenic variants is not typically seen within individuals with acute IAV infection. This apparent disconnect between evolutionary processes at population and within-host scales contributes to the challenge of predicting evolutionary outcomes. The processes that impede IAV selection within the host, and their potency, have not been examined systematically. To address this knowledge gap, we will test the central hypothesis that the genetic structure of within-host viral populations plays a major role in defining the likelihood that a beneficial mutation becomes fixed. In particular, we hypothesize that the fate of a highly fit variant virus is shaped by its initial prevalence in the inoculum (quantitative structure), the timing with which it arises de novo (temporal structure), its location within the infected tissue (spatial structure) and the presence or absence of competing variants (clonal interference). In turn, we predict that onward transmission of a beneficial variant will rely on a combination of these factors and the stringency of the transmission bottleneck. We furthermore propose that the severity of the bottleneck is modulated by pre-existing immunity in the host. To test these hypotheses, we will monitor the dynamics of mixed viral populations containing a seasonal IAV and one or two HA antigenic variants thereof within individual guinea pigs and between transmission partners. Partial immunity will be induced with vaccination to yield a model in which the antigenic variants have a selective advantage. Distinct sequence barcodes will be included in the HA and NA genes of each virus to allow sensitive detection of genetic bottlenecks. Tracking barcodes in both HA and NA will allow genetic linkage to be assessed. The wild type and antigenic variant viruses will be combined in vivo with various quantitative, temporal and spatial structures and then barcode dynamics will be monitored by sequencing. With this approach, we will perform a systematic evaluation of the consequences of population genetic structure for viral evolutionary dynamics. This well-controlled and systematic approach will allow identification of processes that impede selection within and between individual hosts, providing much needed insight into the forces shaping IAV evolution where it begins.

概括 在全球人口水平上，季节性甲型流感病毒（IAV）进化的特点是反复选择性 扫描中，逃避抗体反应的新抗原变体取代了以前流行的菌株。 尽管在群体水平上存在这种明显的模式，但抗原变体的选择通常不会在群体中看到。 患有急性 IAV 感染的个体。人口和进化过程之间明显的脱节 宿主内部尺度有助于预测进化结果的挑战。阻碍的过程 宿主内 IAV 的选择及其效力尚未得到系统研究。为了解决这个问题 为了弥补知识差距，我们将测试宿主内病毒种群的遗传结构发挥作用的中心假设 在定义有益突变固定的可能性方面发挥着重要作用。特别是，我们假设 高度契合的变异病毒的命运取决于其在接种物中的最初流行程度（定量结构）， 它从头出现的时间（时间结构），它在受感染组织内的位置（空间结构） 以及是否存在竞争性变异（克隆干扰）。反过来，我们预测未来 有益变体的传播将取决于这些因素的组合以及严格的要求 传输瓶颈。我们进一步建议，瓶颈的严重性是通过预先存在的来调节的 宿主体内的免疫力。为了检验这些假设，我们将监测混合病毒群体的动态 豚鼠个体和豚鼠个体之间含有季节性 IAV 及其一种或两种 HA 抗原变体 传输合作伙伴。通过疫苗接种诱导部分免疫，产生一个模型，其中抗原 变体具有选择性优势。不同的序列条形码将包含在HA和NA基因中 每种病毒都允许灵敏地检测遗传瓶颈。跟踪 HA 和 NA 中的条形码将允许 待评估的遗传连锁。野生型和抗原变异病毒将在体内与各种不同的病毒结合。 定量、时间和空间结构，然后通过测序监测条形码动态。和 通过这种方法，我们将对人口遗传结构的影响进行系统评估 病毒进化动力学。这种控制良好的系统化方法将允许识别流程 这阻碍了个体宿主内部和个体宿主之间的选择，从而提供了对塑造力量的急需的洞察 IAV 进化由此开始。