Hematopoietic Stem Cell Dysfunction and Regeneration in Severe Infection

项目摘要 严重感染的幸存者往往表现出长期的免疫功能障碍，身体和认知能力下降， 死亡风险显著增加。如何改善重症肌无力幸存者的长期预后 感染具有重要的临床意义，是一个重要的未决问题。在这里，我们将探讨 休克样感染的长期影响，使用蜱传感染和脓毒症模型，对造血系统的影响， 造血干细胞（HSC）功能的问题：严重感染对造血的长期影响是什么？ HSC功能？造血干细胞是否已准备好产生特定的谱系？我们能否在严重的 疾病，以改善幸存者的结果？骨髓微环境（或生态位）如何， HSC驻留，受到严重疾病的影响？ 脓毒症是一种严重的全身性感染，可导致血管功能障碍和器官衰竭， 医院死亡的主要原因。尽管在脓毒症病理生理学的理解方面取得了进展， 治疗方法有限，死亡率仍然很高。与此同时，抗生素耐药性、 媒介传播的病原体以及缺乏针对新出现感染的疫苗是全球感染的重要因素。 增加传染病负担。随着严重感染的不断出现和败血症的发生率 幸存者的数量也在增加。在这里，我们的目标是了解严重的， 急性感染对造血干细胞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HSC和祖细胞，对生命至关重要。的 血液产生的过程产生对宿主防御至关重要的免疫系统细胞，以及所有 氧合（红细胞）和血管止血（血小板）所必需的血液成分。 HSC位于血液系统层级的顶部，处于储备状态，但可以通过激活HSC来激活。 急性炎症产生免疫细胞。目前尚不清楚的是急性炎症性损伤如何影响 干细胞在长期恢复阶段的功能。除了免疫细胞，血液成分 (RBCs和血小板）在宿主防御中发挥着未被充分认识的作用， 和所有组织系统的功能。最终，我们将测试策略，以提高数量和功能 严重传染病幸存者的干细胞。

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.