HSC function during infection

描述(由申请人提供)：HSPC在感染过程中的功能造血干细胞和祖细胞(HSPC)在整个生命周期中具有维持血液生产的基本作用，包括免疫系统的所有细胞。为了应对压力，如感染，HSPC也可以被指示从骨髓(BM)分化并快速动员。我们研究的长期目标是了解HSPC在感染过程中如何发挥作用来促进宿主防御，进而了解HSPC功能障碍是如何导致免疫缺陷的。本研究的目的是：(1)明确干扰素(IFN)在HSPC感染过程中对HSPC功能和动员的生物学影响；(2)确定动员的hPSCs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在感染过程中的功能将导致旨在增强宿主防御和降低疾病严重性的新疗法。尽管IFN是在许多感染过程中产生的，但我们对IFN在感染过程中如何调节HSPC功能知之甚少，特别是在I型和II型感染的情况下。存在IFN。我们有新的证据表明，协调的I型和II型干扰素信号对造血功能是有害的，这种缺陷的机制将得到解决(目标1)。此外，该领域的一个假设是，由于原位分化，HSPC从骨髓动员到感染的外围部位促进了对感染的反应。然而，我们的数据支持一种新的范式，即在感染期间高度调节动员，而动员实际上取决于存在的感染病原体的类型。具体地说，对细胞外病原体的动员增加，对细胞内病原体的反应减少，这一过程被发现依赖于干扰素？我们的小说发现了那个干扰素？实际上可以阻碍HSPC动员表明在某些感染条件下动员确实是有害的。我们建议进一步定义感染期间HSPC动员的控制机制(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以驱动激活的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，这项工作对宿主防御具有重要意义，因为IFN在许多感染和许多慢性炎症性疾病期间产生。这些研究还与改进使用HSPC移植治疗人类疾病的临床策略直接相关。而干扰素的耗尽？使用干扰素可能会增加动员和治疗的效果吗？可能通过改善HSPC的生态位功能来增加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.