Increased susceptibility to tuberculosis in HIV-infected individuals remains a worldwide problem. As susceptibility is high even in subjects with preserved CD4+ T cell count, additional defects in innate immune function may account for increased risk. Alveolar macrophages (AMs) are primary effector cells of lung innate immunity and critical cells in the host response to Mycobacterium tuberculosis (MTb). Preliminary data from our laboratory support the central hypothesis that HIV-1 influences early AM innate receptor-mediated recognition of MTb and disrupts critical host defense signal transduction pathways that contribute to MTb susceptibility and disease pathogenesis. Current concepts suggest that AM inflammatory response to MTb is primarily mediated through Toll-like receptor 2 (TLR2). More recent evidence suggests that TLRs may interact with other pattern recognition receptors to enhance effector cell response. Both mannose receptor and complement receptor 3 are recognized as important receptors in the phagocytosis of virulent MTb. The relative importance of mannose receptor versus complement receptor in enhancing AM response to MTb has not been delineated. Prior work from our lab has revealed that HIV specifically impairs MR phagocytosis and signaling in response to Pneumocystis. The effect of HIV infection on both mannose receptor function and AM response to MTb has not been well studied. This proposal seeks to study the role of mannose receptor in macrophage response to MTb, as well as the effect of HIV infection on mannose receptor function and response to MTb. Using primary human alveolar macrophages, we will investigate the following specific aims:
AIM #1) We will define the relative contribution and interdependence of AM innate pattern recognition receptors (MR, TLR2, CR3) that recognize virulent MTb and mediate pro-inflammatory and apoptotic responses.
AIM #2) Examine the influence of HIV infection on receptor-mediated AM recognition and cellular response to virulent MTb.
AIM #3) We will investigate the role of specific HIV therapy and the use of specific immune-modulating agents to rescue and augment AM innate receptor-mediated recognition of virulent MTb in the context of HIV infection. ? ? This proposal will provide improved understanding of the host response to MTb infection and may identify specific defects in AM host cell response to MTb that lead to novel therapeutic targets. In addition, this proposal will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The present proposal provides the applicant the opportunity to master a broad range of current laboratory techniques in molecular and cellular biology, supplemented by a program of didactic study of immunology. ? ?
