Novel Mechanisms of CD4-Independent Immunity Against Pneumocystis - Pneumocystis pneumonia (PCP) remains a serious life-threatening respiratory fungal infection of immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the world. PCP-related mortality rates have changed little over the past two decades, likely due to our inability to adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is uncertain. The mechanisms by which Pneumocystis (PC) is recognized and cleared from the lung remain incompletely understood. Alveolar macrophages (AMs) are important effectors of pulmonary innate immunity, but they are typically ineffective for host defense against Pneumocystis when CD4+ T cell help is not fully functional. The reason for this is unknown, but it has been suggested that PC actively evades or suppresses macrophage mediated host defense to ensure survival and transmission. Our laboratory has identified an inbred mouse strain which is unique in that it displays robust and rapid innate immunity against PC in the absence of CD4+ T cell function. The resistant phenotype requires AM-dependent removal of PC, but the specific mechanism remains unknown. In vitro studies have failed to reveal distinct differences in the phagocytic potential of resistant and susceptible AMs, leading us to hypothesize that the lung environment and lung epithelial cells (LECs) are critical components of effective innate immunity against PC. To test this hypothesis, we will utilize the resistant and susceptible mouse models described in our preliminary studies. Our long-term goal is to identify the effector mechanisms responsible for FVB protective innate immunity. We predict that the robust and rapid removal of PC from the lungs of FVB mice suggests that once identified, this mechanism might be exploited to design novel strategies that quickly eradicate PC without eliciting immunopathogenesis, providing improved outcomes in HIV and other patients with compromised CD4+ T cell function. In order to advance this goal, we propose two Specific Aims that will: 1) define the early transcriptional profiles of resistant (FVB) and susceptible (Balbc) LECs following the in vivo interaction with PC; and 2) directly determine whether the FVB lung environment, including LECs, is required for effective innate immunity against PC. If the proposed hypothesis is correct, these studies could drive new directions of research into the mechanisms that regulate pulmonary innate immunity.F2
