Intrinsic Programming of Alveolar Macrophages for Protective Antifungal Innate Immunity Against Pneumocystis Infection.
Invasive fungal infections, including Pneumocystis Pneumonia (PcP), remain frequent life-threatening conditions of patients with adaptive immune defects. While innate immunity helps control pathogen growth early during infection, it is typically not sufficient for complete protection against Pneumocystis and other human fungal pathogens. Alveolar macrophages (AM) possess pattern recognition molecules capable of recognizing antigenic and structural determinants of Pneumocystis. However, this pathogen effectively evades innate immunity to infect both immunocompetent and immunosuppressed hosts, albeit with differing outcomes. During our studies of mouse models of PcP, the FVB/N strain was identified as unique because of its ability to mount a protective innate immune response against Pneumocystis infection. In contrast to other immunocompetent strains, which become transiently infected prior to the onset of adaptive immunity, FVB/N mice rapidly eradicated Pneumocystis before an adaptive immune response was triggered. Furthermore, FVB/N mice remained highly resistant to infection even in the absence of functional T cells. The effector mechanism of innate protection required the action of functional alveolar macrophages, and the adoptive transfer of resistant FVB/N AMs, but not susceptible CB.17 AMs, conferred protection to immunodeficient mice. Macrophage IFNγ receptor signaling was not required for innate resistance, and FVB/N macrophages were found to display markers of alternative activation. IFNγ reprogrammed resistant FVB/N macrophages to a permissive M1 biased phenotype through a mechanism that required direct activation of the macrophage IFNγR. These results demonstrate that appropriately programmed macrophages provide protective innate immunity against this opportunistic fungal pathogen, and suggest that modulating macrophage function may represent a feasible therapeutic strategy to enhance antifungal host defense. The identification of resistant and susceptible macrophages provides a novel platform to study not only the mechanisms of macrophage-mediated antifungal defense, but also the mechanisms by which Pneumocystis evades innate immunity.
['Bhagwat|Samir P|SP|', 'Gigliotti|Francis|F|', 'Wang|Jing|J|', 'Wang|Zhengdong|Z|', 'Notter|Robert H|RH|', 'Murphy|Patrick S|PS|', 'Rivera-Escalera|Fátima|F|', 'Malone|Jane|J|', 'Jordan|Michael B|MB|', 'Elliott|Michael R|MR|', 'Wright|Terry W|TW|']
D056704:Adaptive Immunity D000818:Animals D006801:Humans D007113:Immunity, Innate D007121:Immunocompetence D016867:Immunocompromised Host D008264:Macrophages D016676:Macrophages, Alveolar D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D008819:Mice, Nude D016513:Mice, SCID D016720:Pneumocystis Infections D015398:Signal Transduction D013601:T-Lymphocytes
alveolar macrophage innate immunity pneumocystis fungal pathogens mouse models