Strain-Dependent Protective Innate Immunity Against Pneumocystis Pneumonia in Mice

Pneumocystis is a respiratory fungal pathogen that causes life-threatening pneumonia in immunocompromised patients. While Pneumocystis can colonize healthy hosts by resisting and transiently evading innate immunity, a functional adaptive immune response is essential to prevent progressive infection. Impairments in adaptive immunity, particularly defects in CD4⁺ T cell function, are strongly associated with the development of severe Pneumocystis pneumonia (PCP) in humans and a wide range of mammalian species. Immune activation by Pneumocystis has strong genetic determinants, and a major gap in our understanding of PCP pathogenesis lies in uncovering the mechanisms by which Pneumocystis escapes alveolar macrophages and evades pulmonary innate immunity. Prior research determined that FVB/NJ mice display an unusual resistance to Pneumocystis infection. Further susceptibility testing across several inbred mouse strains revealed that the AKR/J strain, which is phylogenetically distant from the FVB/NJ strain, also exhibits a rarely described form of protective innate immunity against PCP. Notably, the mechanism of AKR/J resistance does not require CD4⁺ or CD8⁺ T lymphocytes. However, depleting alveolar macrophages prior to infection rendered AKR/J mice susceptible to PCP, highlighting the critical role of macrophages for this protective innate immune response. These novel findings establish the AKR/J inbred strain as a valuable model for investigating the interaction between Pneumocystis and macrophages, offering a unique opportunity to explore how these interactions lead to differential outcomes between resistant and susceptible mouse strains. Additionally, it may offer key insights into the mechanisms by which Pneumocystis evades macrophage-mediated innate immunity in the majority of mammalian hosts, including humans.