BONE MARROW FAILURE AND IMMUNE RESPONSES TO PULMONARY FUNGAL INFECTIONS

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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.