Despite general advances in patient care, Pneumocystis pneumonia (PcP)-related mortality remains unacceptably high. Therefore, we need better understanding of the biology of the host-pathogen interaction to identify alternative treatment strategies for PcP. T cell-derived signals are critical for host defense against PcP. However, the host's T helper (TH)-mediated immune response also contributes to PcP-related immunopathogenesis. The precise downstream effector mechanisms by which TH cells mediate these processes are undefined, impairing our ability to design optimal therapeutic strategies. Macrophage phenotype and effector functions are regulated by TH cells. TH1 signals induce a classical macrophage activation phenotype (CAM), while TH2 signals produce an alternative activation phenotype (AAM). However, the relative contributions of these distinct macrophage activation programs to host defense and/or immunopathogenesis have not been determined. Our Preliminary Studies demonstrate that it is possible to control macrophage phenotype in response to PcP. For example, administering the anti-inflammatory agent sulfasalazine to mice with PcP resulted in macrophages with an AAM phenotype rather than the CAM phenotype seen in vehicle- treated control mice. Importantly, shifting the response to the TH2/AAM pathway resulted in attenuated PcP- related immunopathogenesis while at the same time enhancing macrophage-mediated Pc clearance. The specific objective of this application is to determine how modulation of alveolar macrophage (AM) phenotype and effector function influences both PcP-related immunopathogenesis and host defense. The overarching hypothesis of this proposal is that AMs are key effectors of both host defense and PcP-related immunopathogenesis, and that directed modulation of macrophage polarization represents a novel therapeutic strategy to improve the outcome of PcP. We will use a combination of pharmacological, immunological, and knockout technologies to determine how differential AM polarization controls the onset, inflammatory, and resolution/repair phases of PcP, and to define the mechanisms of macrophage action. Our long-term goal is to understand the mechanisms regulating innate and adaptive immunity in the lung to facilitate the rational design of therapeuti strategies to enhance host defense while limiting immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) determine how differential macrophage activation regulates the immune response to Pc; 2) identify mechanisms of CD4+ T cell independent resistance to Pc; and 3) evaluate whether modulating AM phenotype is an effective strategy for the treatment of PcP. This proposal is innovative because it focuses on AMs as effectors mediating both immunopathogenesis and host defense. The proposed research is significant because it will enhance our understanding of PcP-related immunopathogenesis, and has the potential to lead to novel therapeutic strategies that can be translated to improve patient care.
By defining the relationship between macrophage phenotype and effector function and how this relationship is regulated during Pneumocystis pneumonia (PcP), this proposal will identify new therapeutic targets to control the tissue-damaging inflammatory response that is the hallmark of PcP. This approach should address the decades-long failure to make major improvements in the outcome of PcP. 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 translational studies designed to improve patient care.
