Abstract
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.
Highlights
Pneumocystis (Pc) is an opportunistic fungal pathogen that causes life-threatening pneumonia (PcP) in immunocompromised individuals, including patients with AIDS, cancer, organ transplants, and certain congenital immunodeficiencies
The key immune cells required for host defense against Pneumocystis are CD4+ T cells [17], and humans, non-human primates, rats, ferrets, and many inbred strains of mice are all highly susceptible to Pneumocystis when CD4+ T cell function is impaired
Despite the fact that these tissue resident cells express pattern recognition molecules capable of recognizing antigenic and structural components of Pneumocystis, they have far proven incapable of providing effective host defense in the absence of CD4+ T cell helper function [11]
Summary
Pneumocystis (Pc) is an opportunistic fungal pathogen that causes life-threatening pneumonia (PcP) in immunocompromised individuals, including patients with AIDS, cancer, organ transplants, and certain congenital immunodeficiencies. The species infecting humans, called P. jirovecii (Pj), is widespread throughout the human population. PcP remains one of the most common AIDS-defining-illnesses [1, 2], and in recent years non-AIDS-related PcP has become more frequently diagnosed in previously unreported clinical settings [3]. Patients receiving long-term immunomodulatory therapies for inflammatory disease may be at particular risk. Persistent colonization with P. jirovecii has been reported, and is a complicating factor in patients suffering from chronic lung disease [4]. Despite improvements in medical care, the mortality rate for patients developing PcP has changed little over the past three decades, and greater understanding of host-pathogen interactions is critical to improving treatment and survival
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