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Type I Interferon Signaling and B Cells Maintain Hemopoiesis during Pneumocystis Infection of the Lung¹

Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT 59718

Loss of CD4 T cells is the hallmark of HIV infection. However, type I IFN-producing plasmacytoid dendritic cells may also be lost. This results in susceptibility to an opportunistic infection such as Pneumocystis pneumonia. In addition, regenerative bone marrow failure resulting in pancytopenia is another common problem in advanced stage AIDS. This may be linked to both the failing immune system and recurrent opportunistic infections. We generated lymphocyte-deficient type I IFN receptor-deficient mice (IFrag^–/–) to study the effects on Pneumocystis infection of the lung. When IFrag^–/– animals were infected with Pneumocystis they died between days 16 and 21 postinfection with minimal pneumonia but severe anemia due to complete bone marrow failure. This included the loss of uncommitted hemopoietic precursor cells. Bone marrow failure was prevented by the reconstitution of IFrag^–/– mice with wild-type lymphocytes, especially B cells. T and B cells lacking type I IFN receptor signaling could only partially prevent bone marrow failure in response to Pneumocystis infection. However, the presence of T and B cells lacking type I IFN signaling resulted in compensatory extramedullary hemopoiesis in the liver and spleen. Lymphocyte support of the regenerative capacity of the bone marrow was provided by both type I IFN-dependent and -independent mechanisms that acted synergistically. Our findings point to the requirement of both type I IFNs and lymphocytes in the regenerative capabilities of the hemopoietic system under the pressure of Pneumocystis infection, but not during steady-state hemopoiesis. This may have implications in the management of pancytopenia in AIDS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL55002 and RP020185.

² Address correspondence and reprint requests to Dr. Nicole Meissner, Department of Veterinary Molecular Biology, Montana State University, 960 Technology Boulevard, Bozeman, MT 59718. E-mail address: nicolem{at}montana.edu

³ Abbreviations used in this paper: HAART, highly active antiretroviral therapy; FLT3, fetal liver tyrosine kinase 3; FLT3L, FLT3 ligand; HSC, hemopoietic stem cell; HPC, hemopoietic precursor cell; KO, knockout; lin, lineage; RANKL, receptor activator of NF-B ligand.

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