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

Area of Science:

• Immunology
• Mycology
• Infectious Diseases

Background:

• Pneumocystis species cause opportunistic infections in immunocompromised individuals.
• FVB/NJ mice exhibit unique innate immunity against Pneumocystis, mediated by alveolar macrophages, even without CD4+ T cells.
• Alveolar macrophages in FVB/NJ mice show an M2-biased phenotype, suggesting a role in infection resistance.

Purpose of the Study:

• To investigate the role of Stat6 signaling in FVB/NJ mice's innate resistance to Pneumocystis infection.
• To determine if Stat6 is essential for the M2 polarization of FVB/NJ alveolar macrophages upon Pneumocystis stimulation.
• To explore alternative pathways involved in macrophage-mediated innate immunity against Pneumocystis.

Main Methods:

• Generation of FVB Stat6-deficient mice (FVB Stat6-/-).
• Assessment of alveolar macrophage M2 polarization in response to Th2 cytokines and Pneumocystis.
• Evaluation of Pneumocystis infection susceptibility in FVB Stat6-/- and FVB MerTK-/- mice.

Main Results:

• FVB Stat6-/- mice remained resistant to Pneumocystis infection, indicating Stat6 dispensability for innate resistance.
• FVB Stat6-deficient alveolar macrophages showed impaired M2 polarization with Th2 cytokines but maintained M2 markers and upregulated M2 genes upon direct Pneumocystis stimulation.
• FVB MerTK-/- mice exhibited only marginally increased susceptibility to Pneumocystis infection.

Conclusions:

• Stat6 signaling is not required for FVB/NJ mice's innate immunity against Pneumocystis.
• Alternative pathways, beyond Stat6, likely regulate the M2 polarization and innate resistance mediated by FVB/NJ alveolar macrophages.
• These findings reveal novel mechanisms of innate immune defense against fungal respiratory pathogens.