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

species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. 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 , 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 , suggesting that macrophage polarization may dictate the outcome of the -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 . Additional FVB/NJ knockout strains were generated, but only FVB MerTK mice showed a marginally increased susceptibility to infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.