Pulmonary Gammaherpesvirus Infection and Pneumonitis Development Following Murine Bone Marrow Transplant.
Pulmonary complications are frequent following hematopoietic stem cell transplantation, including infections and pneumonitis. We have used a murine bone marrow transplant (BMT) model and murine gammaherpesvirus, γHV-68, to study alterations in anti-viral immunity post-transplant. When challenged with γHV-68, BMT mice have reduced ability to control lytic viral replication in the lung, despite immune reconstitution. By day 21 post-infection the virus is latent, and BMT mice, but not control, develop pneumonitis with reduced oxygenation, fibrosis, inflammation, hyaline membranes, and foamy alveolar macrophages, a phenotype which persists 7 weeks post-infection. BMT mice have an increase in cells harvested by bronchoalveolar lavage (BAL), and this population is enriched in neutrophils, CD4, and CD8 cells. BAL fluid from BMT mice at day 21 has increased pro-fibrotic factors, including hydrogen peroxide, nitrite, and transforming growth factor-beta (TGFβ). Defective control of lytic virus infection in BMT mice is not related to impaired leukocyte recruitment or defective antigen presenting cell function. Rather, BMT lungs have decreased numbers of protective Th1 cells and increased numbers of Th17 cells in response to γHV-68. BMT mice are also characterized by an immunosuppressive lung environment at the time of infection that includes overexpression of TGFβ1, prostaglandin-E2, and increased Tregs. Neither pharmacological blockade of prostaglandin synthesis nor depletion of Tregs improved host defense. To understand the role of TGFβ, BMT mice were transplanted with transgenic bone marrow expressing dominant negative TGFβ receptor II in T cells (Tcell-DN-TGFβRII) or under the CD11c promoter (CD11c-DN-TGFβRII), blocking TGFβ signaling in CD4 and CD8 cells or CD11c-expressing cells, respectively. Tcell-DN-TGFβRII BMT mice have restored lytic viral load and improved Th1 response; these mice are largely protected from the pneumonitis phenotype. However, CD11cDN-TGFβRII BMT mice show increased susceptibility to lytic infection, similar to wild type BMT, and are only moderately protected from pneumonitis. Thus, our results indicate that overexpression of TGFβ1 following myeloablative BMT results in impaired T cell responses to viral infection, resulting in increased lytic viral load and pneumonitis. Our data provide new insight into the potential causes of impaired anti-viral immune responses and development of pneumonitis in hematopoietic stem cell transplant patients.