HSC function during infection

描述（由申请人提供）：HSPC在感染期间的功能造血干细胞和祖细胞（HSPC）在维持血液生成（包括免疫系统的所有细胞）方面具有重要作用。响应于应激，例如感染，HSPC也可以被引导分化并从骨髓（BM）快速动员。我们研究的长期目标是了解HSPC功能在感染过程中如何被引导以促进宿主防御，以及反过来，由于HSPC功能障碍如何导致免疫缺陷。这方面的目标是：（1）确定干扰素（IFN）对感染期间HSPC功能和动员的生物学影响，以及（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。更全面地了解HSPC在感染期间的功能将导致针对增加宿主防御和降低疾病严重程度的新疗法。尽管IFN在许多感染过程中产生，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存在。我们有新的证据表明，一致的I型和II型IFN信号是有害的造血功能，和机制，这种缺陷将得到解决（目标1）。此外，本领域的一个假设是HSPC从BM向外周感染部位的动员由于原位分化而促进对感染的应答。然而，我们的数据支持一种新的范式，即动员在感染过程中受到高度调节，动员实际上取决于存在的传染性病原体的类型。具体而言，动员在对细胞外病原体的反应中增加，在对细胞内病原体的反应中减少，发现这一过程依赖于IFN？。我们的小说发现干扰素？实际上可以阻碍HSPC动员，这表明动员在某些感染条件下可能确实是有害的。我们建议进一步确定感染期间控制HSPC动员的机制（目标2），以及HSPC动员对病原体生长和疾病结局的影响（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以驱动活化的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，这项工作是重要的，广泛相关的宿主防御，因为干扰素是在许多感染和许多慢性炎症性疾病。这些研究也与改善使用HSPC移植治疗人类疾病的临床策略直接相关。而IFN的耗竭？可能会增加动员的效果，用干扰素治疗？可以通过改善HSPC生态位功能来增加HSPC的植入。

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.