Pneumocystis (Pc) remains a frequent cause of life-threatening pneumonia (PcP) in immunocompromised patients. The CDC estimates that 7,500 - 10,000 cases per year occur in the United States. Despite the availability of antibiotics, PcP-related mortality rates have changed little over the past two decades. Thus, at risk patients could benefit from new approaches to prevent and treat infection. Immunization, either active or passive, has the potential to do both. We provide preliminary data from mouse models of PcP supporting the benefits of both active and passive immunization, including evidence demonstrating profound immunoregulatory effects of passive immunization. Because the host's immune response clearly makes a major contribution to the pathogenesis of PcP, the immunoregulatory aspects of immunotherapy are particularly attractive areas for study. We have produced three unique monoclonal antibodies (Mabs) with the rare characteristics of both having biological activity against Pc in vivo, and also binding to conserved epitopes on animal and human derived Pc. These are highly interesting antibodies because their cross-reactive nature suggests that: 1) they recognize conserved proteins with critical functions in the Pc life cycle; and 2) we can use animal models to reasonably predict their utility for treating human patients. We have also isolated the molecule, called A12, which is recognized by two of these Mabs, and demonstrated its efficacy as a subunit vaccine to produce a level of protection not previously reported for other Pc vaccine candidates. Further study of the immune recognition to this protein has the potential to lead to novel immunotherapies and improved understanding of mechanisms of protection against Pc. Our goal is to address clinically relevant questions regarding host and Pc factors that determine the response to immunization. We hypothesize that the alveolar macrophage (AM), acting in concert with antibody (Ab), demonstrates both effector and immunoregulatory function by eliminating Pc and shifting the pulmonary environment from one of pro- inflammatory to one of anti-inflammatory characteristics. To accomplish our goal we will: 1) use state of the art imaging technology to test the hypothesis that the AM is critical for the antimicrobial activity of passive immunization against Pc; 2) test he hypothesis that a Fc , IL-10 dependent shift in AM to an M2 phenotype is necessary for the improvement in PcP after passive immunization; 3) test the hypothesis that the final common pathway of vaccine induced protection of the immunocompromised host is mediated by B cell production of Ab; and 4) create isotype variants of our Mabs to determine the contribution of Fc function to the mechanism of anti-microbial and immunoregulatory effects of passive immunotherapy. If validated, our hypotheses should lead to novel therapeutic strategies that enhance fungal clearance while attenuating PcP- related immunopathogenesis.
Pneumocystis pneumonia (PcP) is a serious and common infection in patients with weakened immune systems. Death from PcP occurs in 10-20% of patients overall, and more than half of patients who need to be put on a ventilator die. A vaccine or antibody treatment for PcP could prevent much of the illness due to this organism. The goal of our research is to use mouse models of PcP to characterize the response to antibody treatments we have developed. Because the mouse model closely mimics what happens in humans this project will be critical to the development of antibody based treatments for human Pc infections. The goal of this project is in direct response to the NIH mission statement of the need to generate basic science data that can be developed into treatments to improve patient care.
|Bhagwat, Samir P; Gigliotti, Francis; Wang, Jing et al. (2018) Intrinsic Programming of Alveolar Macrophages for Protective Antifungal Innate Immunity Against Pneumocystis Infection. Front Immunol 9:2131|