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Protective innate immunity against Pneumocystis does not require Stat6-dependent macrophage polarization

Year: 2024

Type: article

Abstract: ABSTRACT Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis , and remain resistant to infection even in the absence of CD4 + T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis , suggesting that macrophage polarization may dictate the outcome of the Pneumocystis –macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6 –/– mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6 –/– mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6 –/– mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis . Additional FVB/NJ knockout strains were generated, but only FVB MerTK –/– mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.

Source: Infection and Immunity

DOI: 10.1128/iai.00222-24

Authors: T. Mousso, S. J. Pollock, P. C. Inzerillo, F. Gigliotti, T. W. Wright

Institutions: University of Rochester Medicine, University of Rochester

Language: English

Topic: Pneumocystis jirovecii pneumonia detection and treatment

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases