HSC function during infection

感染期间HSC的功能

• 批准号: 8689208
• 负责人: KATHERINE C. MACNAMARA
• 金额: $ 30.02万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-16 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689208
• 关键词: Acute; Address; Apoptosis; Bacterial Infections; Behavior; Biological; Blood; Blood Cells; Bone Marrow; Cause of Death; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Chronic; Clinical; Communicable Diseases; Data; Defect; Disease; Disease Outcome; Engraftment; Event; Functional disorder; Goals; Growth; Health; Hematopoietic; Host Defense; Immune System Diseases; Immune response; Immune system; Immunity; Immunotherapy; In Situ; Individual; Infection; Infection Control; Inflammation; Inflammatory; Interferon Receptor; Interferon Type I; Interferon Type II; Interferons; Knowledge; Lead; Life; Lymphoid; Mission; Modeling; Mus; Myelogenous; Organism; Outcome; Output; Pathology; Patients; Peripheral; Predisposition; Process; Production; Public Health; Regulation; Research; Role; Severity of illness; Signal Transduction; Site; Stem cells; Stress; Therapeutic; Tissues; Transplantation; United States; Vaccine Adjuvant; Work; aluminum sulfate; burden of illness; cell type; extracellular; human disease; improved; in vitro Assay; in vivo; mortality; mutant; novel; pathogen; peripheral blood; public health relevance; receptor; research study; response; self-renewal; stem; trafficking

DESCRIPTION (provided by applicant): HSPC Function during Infection Hematopoietic stem and progenitor cells (HSPCs) has the essential role of maintaining blood production, including all cells of the immune system, throughout life. In response to stress, such as infection, HSPCs can also be directed to differentiate and rapidly mobilize from the bone marrow (BM). The long-term goal of our research is to understand how HSPC function is directed during infection to promote host defense and, in turn, how defects in immunity arise due to dysfunction of HSPCs. The objectives here are to: (1) define the biological impact of interferons (IFNs) on HSPC function and mobilization during infection and (2) determine the capacity of mobilized HPSCs to directly control infection. Infectious disease represents a major cause of mortality in the United States and around the world. A more complete understanding of HSPC function during infection will lead to novel therapies geared at increasing host defense and reducing severity of disease. Despite the fact that IFNs are produced during many infections, we know very little about how IFNs regulate HSPC function during infection, particularly when both type I (¿ and ¿) and II (?) IFNs are present. We have new evidence that concerted type I and II IFN signaling is detrimental to hematopoietic function, and the mechanisms that underlie this defect will be addressed (Aim 1). Furthermore, an assumption in the field has been that mobilization of HSPCs from the BM to peripheral sites of infection promotes responses to infection due to in situ differentiation. However, our data supports a new paradigm whereby mobilization is highly regulated during infection, and mobilization actually depends upon the type of infectious pathogen present. Specifically, mobilization is increased in response to extracellular pathogens and decreased in response to intracellular pathogens, a process found to be dependent on IFN?. Our novel finding that IFN? can actually impede HSPC mobilization suggests that mobilization may indeed be harmful in some infection conditions. We propose to further define the mechanisms controlling HSPC mobilization during infection (Aim 2), and the impact of HSPC mobilization on pathogen growth and disease outcome (Aim 3). These studies will provide a new framework in which to understand host defense and pathology. The possibility of manipulating IFNs during acute infection to drive lineage-fate choices of activated HSPCs and/or direct HSPC mobilization has tremendous therapeutic potential. Thus, this work is significant and broadly relevant to host defense as IFNs are produced during many infections and during many chronic inflammatory diseases. These studies are also directly relevant to improving clinical strategies that use transplantation of HSPCs to treat human diseases. Whereas the depletion of IFN? will likely increase the efficacy of mobilization, treatment with IFN? may augment engraftment of HSPCs by improving the HSPC niche function.

描述（由申请人提供）：感染期间的 HSPC 功能 造血干细胞和祖细胞 (HSPC) 在整个生命过程中维持血液生成（包括免疫系统的所有细胞）方面发挥着重要作用。为了应对感染等压力，HSPC 也可以被引导分化并从骨髓 (BM) 中快速动员。我们研究的长期目标是了解感染过程中 HSPC 功能如何被引导以促进宿主防御，以及反过来，HSPC 功能障碍如何导致免疫缺陷。这里的目标是：(1) 确定干扰素 (IFN) 对感染期间 HSPC 功能和动员的生物学影响；(2) 确定动员的 HPSC 直接控制感染的能力。传染病是美国和世界各地死亡的主要原因。对感染期间 HSPC 功能的更全面了解将带来旨在增强宿主防御和降低疾病严重程度的新疗法。尽管许多感染过程中都会产生 IFN，但我们对 IFN 在感染过程中如何调节 HSPC 功能知之甚少，特别是当 I 型（¿ 和 ¿）和 II 型（？） IFN 都存在时。我们有新的证据表明，协调一致的 I 型和 II 型 IFN 信号转导对造血功能有害，并且将解决这种缺陷背后的机制（目标 1）。此外，该领域的一个假设是，由于原位分化，HSPC 从 BM 动员到感染周围部位会促进对感染的反应。然而，我们的数据支持一种新的范式，即在感染过程中动员受到高度调控，而动员实际上取决于存在的传染性病原体的类型。具体而言，动员响应细胞外病原体而增加，并响应细胞内病原体而减少，发现这一过程依赖于IFNα。我们的新发现是干扰素？实际上会阻碍 HSPC 动员，这表明动员在某些感染情况下确实可能有害。我们建议进一步明确感染期间控制 HSPC 动员的机制（目标 2），以及 HSPC 动员对病原体生长和疾病结果的影响（目标 3）。这些研究将为理解宿主防御和病理学提供一个新的框架。在急性感染期间操纵 IFN 来驱动活化 HSPC 的谱系命运选择和/或直接 HSPC 动员的可能性具有巨大的治疗潜力。因此，这项工作与宿主防御具有重要且广泛的相关性，因为干扰素是在许多感染和许多慢性炎症性疾病期间产生的。这些研究还与改进利用 HSPC 移植治疗人类疾病的临床策略直接相关。而干扰素的消耗呢？可能会增加动员、干扰素治疗的疗效吗？可以通过改善 HSPC 生态位功能来增强 HSPC 的植入。