The natural killer cell response against mouse cytomegalovirus infection

项目摘要 自然杀伤（NK）细胞是保护宿主免受病毒侵害的细胞毒性先天性淋巴细胞。新生儿和 缺乏NK细胞的免疫功能低下的个体，对病毒感染极其敏感，包括 疱疹病毒如人巨细胞病毒（HCMV）。HCMV可以使用小鼠精确建模 巨细胞病毒（MCMV）感染小鼠，这是一个强大的系统，研究抗病毒NK细胞 应答从上一个R01资助期开始，我的实验室发现了新的细胞和分子 NK细胞对MCMV应答的潜在机制。当前的R01更新旨在了解 抗病毒NK细胞应答的转录组学、表观遗传学和代谢控制，研究集中在 转录因子IRF4的新作用。在令人兴奋的初步数据中，我们发现IRF4在NK细胞中被快速诱导， 细胞在MCMV感染期间，并在其效应反应中起关键作用。对于所提出的实验， 我们已经产生了具有条件性Irf4消融的新的转基因小鼠。在目标1中，我们将确定IRF4是如何 在活化的NK细胞中转录和表观遗传调节，并测试IRF4缺陷如何影响 NK细胞抗MCMV感染的功能。目的2将确定新的基因靶点和IRF4的结合伴侣 在NK细胞中通过整合转录组学、表观遗传学和蛋白质组学方法。在目标3中，我们将研究 IRF4是否通过控制整体代谢和线粒体健康来驱动抗病毒NK细胞应答。 总之，R01更新的研究将促进我们对这些分子基础的理解。 强大的效应细胞可以介导对病原体入侵的保护，并建立创新的临床 NK细胞如何被用于对抗感染性疾病的治疗策略的范例。

Project Summary Natural killer (NK) cells are cytotoxic innate lymphocytes that protect the host against viruses. Newborns and immunocompromised individuals lacking NK cells and are extremely susceptible to viral infection, including herpesviruses such as human cytomegalovirus (HCMV). HCMV can be accurately modeled using mouse cytomegalovirus (MCMV) infection in mice, which represents a robust system for investigating antiviral NK cell responses. From the previous R01 funding period, my lab has discovered new cellular and molecular mechanisms underlying NK cell responses against MCMV. This current R01 renewal seeks to understand the transcriptomic, epigenetic, and metabolic control of the antiviral NK cell response, with studies centering around a novel role for the transcription factor IRF4. In exciting preliminary data, we find IRF4 is rapidly induced in NK cells during MCMV infection and plays a critical role in their effector response. For the proposed experiments, we have generated new transgenic mice with conditional Irf4 ablation. In Aim 1, we will determine how IRF4 is transcriptionally and epigenetically regulated in activated NK cells, and test how IRF4-deficiency impacts the function of NK cells against MCMV infection. Aim 2 will identify novel gene targets and binding partners of IRF4 in NK cells by integrating transcriptomic, epigenetic, and proteomic approaches. In Aim 3, we will investigate whether IRF4 drives antiviral NK cell responses by controlling overall metabolism and mitochondrial health. Altogether, the studies in this R01 renewal will advance our understanding of the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion, and establish innovative clinical paradigms for how NK cells may be harnessed for therapeutic strategies against infectious disease.