Memory T cell protection of reproductive health following influenza infection

项目摘要 呼吸道感染是世界范围内的主要死亡原因。受损的细胞免疫 反应、疫苗效力低和疫苗接种率低都增加了严重感染的可能性 在接触甲型流感病毒(IAV)等呼吸道病毒后，孕妇继而感染； 大约80%的孕妇有患流感相关并发症的高风险。我们最好的辩护 就是接种疫苗。疫苗诱导的保护是由免疫记忆介导的。免疫学上的大多数 到目前为止，记忆研究主要集中在抗病原体防御的分化、存活和描绘上。 病原体特异性T细胞在正常生理环境下使用的机制。网络的影响 令人惊讶的是，怀孕对记忆T细胞的持久性和功能回忆潜力尚不清楚。 这一建议的主要假设是，IAV特异性T细胞记忆在 受孕将在整个怀孕期间发挥强有力的普遍、异型保护作用。这一假说产生了 根据我们的观察，从流感感染的肺中分离出的记忆效应CD4T细胞表达低水平 雌激素和孕激素受体与主要效应细胞CD4T细胞的比较。怀孕 众所周知，激素对主要抗病毒药物的产生和功能有不利影响。 免疫反应。这里的初步研究结果表明，异亚型回忆反应确实具有保护性 在怀孕前准备好的怀孕动物身上。在第一个目标中，IAV特异性CD4和CD8的持久性 怀孕期间的记忆T细胞，以及它们分化为许多保护性亚群的能力 将确定介导多种和强大的抗病毒效应功能。我们之前的研究表明，记忆 CD4T细胞调节局部和全身的抗病毒炎症反应，此外，还动员先天的 病原体感染期间的淋巴样细胞。在组织修复中起作用的先天淋巴样细胞最近 已被证明存在于胎盘组织中。在第二个目标中，我们将因此阐明IAV特异性的作用 记忆T细胞通过全身性调节保护胎盘和胎儿的健康发育 IAV感染后的先天炎症和细胞反应。 从提出的反机制研究中获得的洞察力将提高我们的发展能力 改进的疫苗诱导记忆T细胞，能够协调保护性抗病毒防御 怀孕了。这项研究还可能导致开发治疗孕妇的新策略 患有严重流感，目前缺乏治疗选择。呼吸道感染与 甲型流感病毒仍然是一个严重的公共卫生问题，特别是对孕妇来说，她们遭受了 在过去的流行病和大流行季节，发病率和死亡率高得不成比例。拟议的研究已经 对人类生殖健康产生广泛和重大的翻译影响的潜力。

Project Summary Respiratory tract infections are a leading cause of death worldwide. Compromised cell-mediated immune responses, low vaccine efficacy, and poor vaccine uptake all increase the likelihood that serious infection will ensue in pregnant women following exposure to respiratory viruses such as Influenza A virus (IAV); approximately 80% of pregnant women are at high risk for influenza-associated complications. Our best defense is vaccination. Vaccine-induced protection is mediated by immunological memory. The majority of immunological memory studies to date have focused on the differentiation, survival, and delineation of the antipathogen defense mechanisms employed by pathogen-specific T cells under normal physiological circumstances. The impact of pregnancy on the persistence and functional recall potential of memory T cells is surprisingly unknown. The overarching hypothesis of this proposal is that IAV-specific T cell memory generated prior to conception will mediate potent universal, heterosubtypic protection throughout pregnancy. This hypothesis arose from our observations that memory effector CD4 T cells isolated from influenza infected lungs express low levels of estrogen and progesterone hormone receptors in comparison to primary effector CD4 T cells. Pregnancy hormones are well known to have detrimental impacts on the generation and function of primary anti-viral immune responses. Preliminary findings herein show that heterosubtypic recall responses are indeed protective in gravid animals primed prior to conception. In the first aim, the persistence of IAV-specific CD4 and CD8 memory T cells during pregnancy, as well as their ability to differentiate into the many protective subsets that mediate diverse and potent anti-viral effector functions will be determined. Our prior work has shown that memory CD4 T cells regulate both local and systemic anti-viral inflammatory responses, and, additionally, mobilize innate lymphoid cells during pathogen infection. Innate lymphoid cells, which function in tissue repair, have recently been shown to be present in placental tissue. In the second aim, we will thus elucidate the role of IAV-specific memory T cells in preserving both healthy placental and fetal development through the regulation of systemic innate inflammatory and cellular responses following IAV infection. The insight gained from the proposed, `reverse-mechanism', studies will advance our ability to develop improved vaccines that elicit memory T cells capable of orchestrating protective anti-viral defenses during pregnancy. This research may also lead to the development of novel strategies to treat expectant mothers suffering from serious influenza for which current therapeutic options are lacking. Respiratory tract infection with Influenza A virus remains a serious public health concern, particularly for pregnant women, who have suffered disproportionally high morbidity and mortality in past epidemic and pandemic seasons. The proposed study has the potential to make a broad and significant translational impact on human reproductive health.