BONE MARROW FAILURE AND IMMUNE RESPONSES TO PULMONARY FUNGAL INFECTIONS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 骨髓衰竭(BMF)可发生在人类遗传性和获得性疾病的背景下。遗传性疾病与免疫功能不佳和骨缺陷有关，被认为是由炎症引起的。免疫缺陷导致对非典型真菌感染的易感性。肺孢子虫(PC)是一种影响免疫受损宿主的机会性肺部真菌病原体。它见于免疫缺陷和其他免疫缺陷的患者。免疫功能低下的患者在疾病进展过程中也会发生再生性BMF；然而，其机制尚不清楚。我们最近证实，先天的I型干扰素系统在调节肺部和全身对肺炎衣原体肺部感染的反应中起着至关重要的作用。肺炎衣原体肺部感染在I型干扰素受体(IFNAR-/-)和淋巴细胞(RAG-/-)缺乏的IFRAG-/-小鼠中导致快速进展的BMF。它还会导致淋巴细胞功能正常的IFNAR-/-小鼠骨髓抑制和髓外造血。无论是具有完整IFNAR的淋巴细胞缺陷小鼠(RAG-/-小鼠)还是淋巴细胞功能正常的野生型小鼠都没有经历类似的变化。其他肺部真菌感染，如新型隐球菌(Crypto)，不会导致IFRAG-/-小鼠骨髓衰竭。IFRAG-/-小鼠BM失败的原因是所有成熟和前体BM细胞加速凋亡，以及丢失的细胞缺乏补充。我们还发现，与RAG-/-小鼠相比，IFRAG-/-小鼠的骨髓衰竭与骨密度的丧失有关，这是因为与RAG-/-小鼠相比，沿着小梁骨的破骨细胞活性增加。骨骼的变化可能会影响骨骼造血干细胞的生态位，从而影响造血系统的更新能力。我们目前正在研究IFRAG-/-小鼠的骨代谢变化是否与BMF有因果关系，以及在缺乏诱导这种反应的IFNAR信号的情况下，肺内的局部炎症反应是如何偏离的。这对于理解具有遗传或获得性免疫缺陷的炎症诱导的BMF的机制具有重要意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Bone marrow failure (BMF) can occur in the context of inherited and acquired conditions in humans. Inherited conditions are associated with poorly characterized immune and bone-defects and are thought to be inflammation-induced. Immune-defects lead to susceptibilities to atypical fungal infections. Pneumocystis (PC) is an opportunistic pulmonary fungal pathogen affecting the immune compromised host. It is seen in patients with immuno deficiencies and other immune defects. Immuno- compromised patients also develop regenerative BMF during disease progression; however, the mechanisms are poorly understood. We recently demonstrated that the innate type I interferon (IFN) system plays a crucial role in the regulation of pulmonary and systemic responses to PC lung infection. PC lung infection results in rapidly progressing BMF in IFrag-/- mice deficient for both, type I IFN receptor (IFNAR-/-) and lymphocytes (RAG-/-) mice. It also causes BM depression and extramedullary hematopoiesis in lymphocyte-competent IFNAR-/- mice. Neither lymphocyte-deficient mice with intact IFNAR (RAG-/- mice) nor lymphocyte-competent wild-type mice experience similar changes. Other pulmonary fungal infections, such as Cryptococcus neoformans (Crypto), did not cause BM failure in IFrag-/- mice. BM failure in IFrag-/- mice results from accelerated apoptosis of all mature and precursor BM cells and the lack of replenishment of lost cells. We also found that BM failure in IFrag-/- mice is associated with loss of bone density, due to increased osteoclast activity along the trabecular bone when compared to RAG-/- mice. Bone changes are likely to affect the skeletal hematopoietic stem cell niche and, therefore, renewal capacity of the hematopoietic system. We are currently investigating whether bone metabolic changes in IFrag-/- mice are causally linked to BMF and how the local inflammatory response in the lung is deviated in the absence of IFNAR-signaling to elicit this response. This has implications in understanding mechanisms of inflammation-induced BMF with inherited or acquired immunological defects.