Common Post-Infectious Premature Epigenetic Aging

项目概要： 去年在美国，有130万例肺炎病例（不包括 covid 19）。去年全球范围内，分别有4900万例。即使在成功 治疗、肺炎和其他严重感染与死亡率增加>3倍相关 心血管疾病、癌症和复发性感染的风险增加。 我们小组和其他人的初步证据表明，这些严重的 感染会诱发有害的过早表观遗传疤痕，从而加速与年龄相关的疤痕 表观遗传扰动和诱导病理性炎症和降低免疫 响应能力。虽然其他研究已经确定了感染后过早衰老，但这项研究 将是第一个确定哪些感染后过早老化的表观遗传疤痕相关 感染后死亡率、炎症和免疫反应性降低。 我们以前发现，感染后有害的表观遗传疤痕持续至少6 个月长期随访的研究证实，这些表观遗传性疤痕仍然存在。 在最初的损伤消退后82周存在。因此，我们将跟踪参与者， 严重肺炎24个月后完成成功的治疗，并利用 尖端的单细胞测序，以阐明这些有害的疤痕是如何持续存在的， 传播。 我们的初步体外数据表明，感染诱导的过早表观遗传 衰老和免疫紊乱可以通过抑制TCA循环的药物来缓解， 二甲双胍、依维莫司和二甲双胍。本研究将实施机制研究， TCA的抑制剂如何用于减轻感染后过早的表观遗传疤痕 并恢复免疫反应。

Project Summary: Last year in the United States, there were 1.3 million cases of pneumonia (excluding covid19). Worldwide, last year, there were 49 million cases respectively. Even after successful therapy, pneumonia and other severe infections are associated with >3-fold increased mortality risk due to increased cardiovascular disease, cancer, and recurrent infections. Preliminary evidence by our group and others have demonstrated that these severe infections induce detrimental premature epigenetic scars that accelerate age-associated epigenetic perturbations and induce pathologic inflammation and decrease immune responsiveness. While other studies have identified post-infectious premature aging, this study will be the first to identify which post-infectious premature aging epigenetic scars are associated with post-infectious mortality, inflammation and decreased immune responsiveness. We previously identified that post-infectious detrimental epigenetic scars last at least 6 months. Studies with longer-term follow up have confirmed these epigenetic scars are still present 82 weeks after resolution of the original insult. Therefore, we will follow participants with severe pneumonia for 24-months after completion of successful therapy and make use of cutting-edge single cell sequencing to clarify how these detrimental scars are persistently propagated. Our preliminary in vitro data demonstrates that infection induced premature epigenetic aging and immune perturbations can be mitigated by drugs that inhibit the TCA cycle such as metformin, everolimus, and metformin. This study will implement mechanistic studies to explore how inhibitors of the TCA can be used to alleviate post-infectious premature epigenetic scars and restore immune responsiveness.