In AIDS patients'susceptibility to opportunistic infections, such as Pneumocystis Pneumonia (PCP), occurs due to the loss of CD4 T cells and type I interferon (type-I-IFN) producing plasmacytoid dendritic cell (pDC). These infections contribute greatly to morbidity and mortality. An additional and seemingly independent problem in AIDS is the occurrence of progressive pancytopenia (reduction of all blood cells) due to regenerative bone marrow failure. Mechanisms of pancytopenia are poorly understood. Pancytopenia commonly occurs during later stages of AIDS. Therefore, a direct link between the failing immune system and opportunistic infections may exist. We generated mice lacking both a functional type-I-interferon receptor (IFNAR) and T and B cells (referred to as IFrag-/- mice) by crossing IFNAR-/- and RAG-/- mice. We found that Pneumocystis (PC) lung infection in IFrag-/- mice results in a rapidly progressing pancytopenia due to complete bone marrow failure due to increased bone marrow cell apoptosis. In contrast T and B cell deficient RAG-/- mice with intact IFNAR demonstrated normal hematopoiesis during the course of infection and lymphocyte-competent but IFNAR- deficient IFNAR-/- mice showed depressed hematopoiesis in response to PC infection. Immune reconstitution of IFrag-/- mice with wildtype splenocytes or purified B cells prevented bone marrow failure in response to the infection. Immune reconstitution of IFrag-/- mice with splenocytes from IFNAR-/- donor mice resulted in only partial rescue of hematopoiesis following PC lung infection. Bone marrow chimera experiments between IFrag- /- and RAG-/- mice revealed that IFNAR expression is required on hematopoietic cells but not on stromal cells in order to maintain hematopoiesis during PC lung infection. Our hypothesis is that type-I-IFNs, supported by B cells, maintain hematopoiesis during the pressure of opportunistic infections such as PC infection of the lung by affecting the HSC niche and balance proliferative versus pro-apoptotic signals initiated by the systemic acute phase response. To validate this hypothesis, we propose the following specific studies: 1) Determine whether the lack of type I IFN-signaling affects the bone marrow microenvironment by initiating a misbalance between pro-apoptotic and pro-proliferative signals. 2) Determine the mechanisms by which B cells act to maintain medullar and induce extra-medullar hematopoiesis. 3) Determine how the innate immune response of the lung is altered in IFrag-/- mice compared to RAG-/- mice and how this may determine the bone marrow response These studies should lead to a better understanding between connections of immune responses to specific pathogens and maintenance of hematopoiesis during these acute stress responses. This may have implications in the management of pancytopenia during complex immunodeficiencies such as AIDS.

Public Health Relevance

Our proposal is to study how the type-I-interferon system and the acquired immune system support hematopoiesis (blood cell production) when under the stress of Pneumocystis pneumonia. During the course of AIDS, patients suffer from recurrent infections such as Pneumocystis pneumonia as well as pancytopenia, a broad deficiency of all blood cell components. Our mouse model would be further developed in this proposed grant demonstrating loss of the type-I-interferon system and acquired immune system resulting in pancytopenia due to bone marrow failure, when under the stress of Pneumocystis. Understanding how the immune system supports hematopoiesis is needed to develop strategies for the prevention and treatment of pancytopenia in AIDS patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Caler, Elisabet V
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Montana State University - Bozeman
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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