Hematopoietic Stem Cell Dysfunction and Regeneration in Severe Infection

项目摘要 严重感染的幸存者通常表现出长期的免疫功能障碍，身体和认知能力下降， 并显著增加了死亡风险。如何改善重症救治幸存者的长期预后 感染具有重要的临床意义，是一个重要的开放问题。在这里，我们将探索 采用壁虱感染和败血症模型的休克样感染对造血系统的长期影响 干细胞(HSC)的功能：严重感染对造血的长期影响是什么 和HSC的功能呢？造血干细胞是否为产生特定血统做好了准备？我们能在严重的情况下保护HSCs吗 疾病可以改善幸存者的预后吗？骨髓微环境(或生态位)如何，在哪里 肝星状细胞居住，受到严重疾病的影响？ 脓毒症是一种严重的全身性感染，会导致血管功能障碍和器官衰竭，是一种 医院死亡的主要原因。尽管对脓毒症的病理生理学研究取得了进展， 治疗手段有限，死亡率居高不下。与此同时，抗生素耐药性的蔓延， 媒介出生的病原体，以及缺乏针对新出现的感染的疫苗是全球 增加传染病负担。随着严重感染的不断出现和败血症的比率 增加了，幸存者的数量也增加了。在这里，我们的目标是了解严重的、 急性感染对HSCs功能及恢复期造血功能的影响 严重感染后健康状况下降。 持续和平衡的血液生产依赖于造血干细胞和祖细胞，是生命所必需的。这个 血液生产过程产生对宿主防御至关重要的免疫系统细胞，以及所有 供氧(红细胞)和血管止血(血小板)所必需的血液成分。 造血干细胞位于血液系统层次结构的顶端，处于储备状态，但可以通过以下方式激活 急性炎症产生免疫细胞。尚不清楚的是急性炎症性侮辱会对 干细胞在长期恢复阶段的功能。除了免疫细胞，血液成分 (红细胞和血小板)在宿主防御中的作用被低估，但对再生很重要 以及所有组织系统的功能。最终，我们将测试改进数量和功能的策略 严重传染病幸存者体内干细胞的数量。

Project Summary Survivors of severe infection often exhibit prolonged immune dysfunction, physical and cognitive decline, and significantly elevated risk of mortality. How to improve long-term outcomes of survivors of severe infection is of major clinical significance and represents an important open question. Here, we will explore the long-term impact of shock-like infection, using models of tick-born infection and sepsis, on hematopoietic stem cell (HSC) function by asking: What are the long-term impacts of severe infection on hematopoiesis and HSC function? Are HSCs primed to produce particular lineages? Can we protect HSCs in severe disease to improve outcomes in survivors? How is the bone marrow microenvironment (or niche), where HSCs reside, impacted by severe disease? Sepsis is a severe systemic infection that causes vascular dysfunction and organ failure, and represents a major cause of mortality in hospitals. Despite advances in understanding of sepsis pathophysiology, treatments are limited, and mortality remains high. At the same time, antibiotic resistance, the spread of vector born pathogens, and the lack of vaccines for emerging infections are important factors in the global increase in infectious disease burden. As serious infections continue to emerge and rates of sepsis have increased, so has the number of survivors. Here, we aim to understand the biological impact of severe, acute infection on the function of HSCs and hematopoiesis during recovery, to provide new insight into the decline in health after serious infection. Continuous and balanced blood production relies on HSCs and progenitors and is essential for life. The process of blood production generates cells of the immune system critical for host defense, as well as all blood components necessary for oxygenation (red blood cells) and vascular hemostasis (platelets). HSCs are positioned at the top of the blood system hierarchy, held in reserve, but can be activated by acute inflammation to produce immune cells. What is unknown is how acute inflammatory insults impact stem cell function in the long-term stages of recovery. In addition to immune cells, blood components (RBCs and platelets) play underappreciated roles in host defense and are important for regeneration and function of all tissue systems. Ultimately, we will test strategies to improve the number and function of stem cells in survivors of severe infectious illness.