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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090488-03
Application #
8041036
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Peavy, Hannah H
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$356,250
Indirect Cost
Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
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Prigge, Justin R; Hoyt, Teri R; Dobrinen, Erin et al. (2015) Type I IFNs Act upon Hematopoietic Progenitors To Protect and Maintain Hematopoiesis during Pneumocystis Lung Infection in Mice. J Immunol 195:5347-57
Searles, Steve; Gauss, Katherine; Wilkison, Michelle et al. (2013) Modulation of inflammasome-mediated pulmonary immune activation by type I IFNs protects bone marrow homeostasis during systemic responses to Pneumocystis lung infection. J Immunol 191:3884-95
Wilkison, Michelle; Gauss, Katherine; Ran, Yanchao et al. (2012) Type 1 interferons suppress accelerated osteoclastogenesis and prevent loss of bone mass during systemic inflammatory responses to Pneumocystis lung infection. Am J Pathol 181:151-62
Taylor, David; Wilkison, Michelle; Voyich, Jovanka et al. (2011) Prevention of bone marrow cell apoptosis and regulation of hematopoiesis by type I IFNs during systemic responses to pneumocystis lung infection. J Immunol 186:5956-67
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