Determinants of antibody-based host resistance against Pneumocystis carinii

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DESCRIPTION (provided by applicant): Pneumocystis carinii (PC) pneumonia is an opportunistic infection found among HIV-infected patients worldwide. Most infants develop PC-specific antibodies by two years of age, underscoring the frequency at which PC is encountered environmentally. Immuno-intact murine hosts mount protective immune responses leading to subclinical infection, while SCID, CD4 T cell deficient, or B cell deficient mice succumb to PC pneumonia. Yet, mice challenged with PC and thereafter depleted of CD4 T cells resist pneumonia, correlating with high titers of PC specific antibody. While CD4+ T cells appear to be critical in the generation of protective antibodies against PC, maintenance of protective antibodies by memory B cells has not been explored. Further, the specific targets of PC-immunoprotective antibodies have not been fully characterized, particularly their affinity for carbohydrate epitopes, which have recently been shown to be critical in vaccine-based resistance against other opportunistic fungal pathogens. The goal of our efforts is to evaluate the mechanisms whereby antibody based immunity may prevent PC infection, and we approach our studies through two aims. Specific Aim I will evaluate the generation of humoral-mediated immunologic memory against PC through characterization of the kinetics of antibody recall responses in the presence or absence of CD4+ T cells. We will also explore the potential of memory B cells to activate in a CD4+ independent environment and reconstitute PC immunity in SCID mice. Specific Aim II will evaluate whether PC infection elicits specific antibodies against the major surface carbohydrates beta-glucan, mannose, and chitin, and whether memory antibody responses are manifested against these epitopes. Given the affinity of the pattern recognition receptor dectin-1 for PC beta-glucan, we will evaluate whether an antibody-like immunotherapeutic consisting of the extracellular domain of dectin-1 fused to the murine lgG1 Fc fragment enhances PC clearance in SCID mice. Greater understanding of the determinants underlying Pneumocystis-specific humoral immunity and its maintenance will inform on resistance mechanisms against this environmental pathogen and will allow us to optimally vaccinate against PC pneumonia in immunodeficient hosts. PC is a commonly encountered environmental fungus causing lethal pneumonia in HIV+ patients, and little is understood as to how antibodies may prevent infection. Our studies will evaluate the molecules that PC antibodies recognize, and the manner whereby antibody-producing cells remember previous PC exposures, providing insight into normal host resistance and the requirements for vaccine design in the setting of HIV.