Evaluation of CC mice as an improved model for influenza immunity

流感感染是一种反复出现的公共卫生负担和我们目前应对季节性流感的策略 接种疫苗提供了次佳的保护。因此，至关重要的是提供对 在动物模型中进行的通用流感疫苗的可能性，许多工作致力于 诱导广谱中和抗体的策略。然而，在没有中和抗体的情况下， 针对保守病毒蛋白如NP或M2的IAV特异性记忆CD8 T细胞的存在， 与控制病毒滴度和减少人类和小鼠的疾病症状有关。小鼠模型 提示是肺内常驻记忆CD8 T细胞(Trm)对IAV感染具有强大的保护作用。 大多数流感免疫学动物模型依赖于可用于研究 近亲繁殖的小鼠。然而，我们自己的数据表明，在人类和近亲繁殖中表现出来的遗传多样性 小鼠，可以显著影响T细胞对流感的反应。因此，将遗传多样性引入小鼠 流感免疫模型可能提供更好的翻译洞察力以及机制 信息。然而，每一只远缘繁殖的老鼠都是独一无二的，这降低了它们的实用性。为了解决这个问题，我们建议 评价遗传多样性协同杂交(CC)小鼠作为一种潜在的改良动物模型 流感免疫力。CC小鼠表现出近乎近亲繁殖，但完全具有特征的遗传多样性，然而， 由于创造性的育种方法，每个CC系实际上都是近交系，可以重复使用 研究，与其他CC品系异交，以进一步增强遗传多样性和遗传图谱研究。我们的 长期目标是确定CC小鼠模型是否提供了对IAV生物学的改进见解- 以及如何操纵这些细胞来增强免疫力以帮助发展 通用流感疫苗。我们将通过以下具体目标来实现这一长期目标： 特定目的-确定CC小鼠的遗传多样性是否会调节IAV特异性循环和肺 驻留记忆CD8 T细胞反应，从而导致改进的IAV免疫动物模型 反映了远亲繁殖人类的遗传多样性。

Influenza infection is a recurring public health burden and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines, as carried out in animal models, and much work is devoted to strategies to induce broadly neutralizing antibodies. However, in the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, correlate with control of viral titers and reduction of disease symptoms in humans and mice. Mouse models suggest it is the lung resident memory CD8 T cells (Trm) that enable robust protection against IAV infection. Most animal models of influenza immunology rely on the sophisticated tools available for studies of inbred mice. However, our own data suggest that genetic diversity, as manifested in humans and outbred mice, can markedly affect T cell responses to influenza. Thus, incorporating genetic diversity into mouse models of influenza immunity may provide improved translational insights along with mechanistic information. However, each outbred mouse is unique, diminishing their utility. To address this, we propose to evaluate the genetically diverse Collaborative Cross (CC) mice as a potentially improved model of influenza immunity. The CC mice exhibit near outbred, but fully characterized genetic diversity, however, due to the creative breeding approach, each CC line is actually inbred and can be used for repeated studies, outcrossing to other CC lines to further enhance genetic diversity and genetic mapping studies. Our long-term goal is to determine if the CC mouse model provides improved insights into the biology of IAV- induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aim: Specific Aim - Determine if genetic diversity in the CC mice will modulate IAV-specific circulating and lung resident memory CD8 T cell responses and thus, result in an improved animal model of IAV immunity that reflects the genetic diversity in outbred humans.