GM-CSF orchestrates monocyte and granulocyte responses to Cryptococcus gattii

Area of Science:

• Immunology
• Infectious Diseases
• Mycology

Background:

• Cryptococcus gattii is an emerging fungal pathogen causing invasive infections.
• Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) are found in some patients with C. gattii infections.
• The role of GM-CSF in C. gattii pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of GM-CSF (CSF2) in the host response to C. gattii infection using a murine model.
• To elucidate the mechanisms by which GM-CSF influences immune cell populations and their function during infection.

Main Methods:

• Comparison of survival and lung fungal burden in wild-type (WT) and Csf2-/- mice infected with C. gattii.
• Depletion of monocyte-derived macrophages (moMacs) in CCR2-DTR+ mice.
• Assessment of macrophage polarization (M1/M2) in response to C. gattii.
• Depletion of neutrophils in Mrp8cretg iDTR+ mice.
• Analysis of immune cell infiltration, including eosinophils and neutrophils, in infected lungs.

Main Results:

• Csf2-/- mice exhibited significantly improved survival and reduced lung fungal burden compared to WT mice.
• GM-CSF promotes monocyte differentiation into alveolar and interstitial macrophages.
• Ablation of moMacs phenocopied the improved survival and reduced fungal burden observed in Csf2-/- mice.
• Macrophages from infected WT mice were unable to undergo M1 polarization, suggesting they become permissive for fungal proliferation.
• GM-CSF and moMacs promoted eosinophil influx over neutrophils and hindered neutrophil entry, impacting fungal clearance.

Conclusions:

• GM-CSF plays a detrimental role in anti-fungal responses to C. gattii.
• GM-CSF mediates harmful immune responses by promoting the differentiation of immunosuppressive monocyte-derived macrophages.
• GM-CSF and moMacs impair host defense by modulating granulocyte recruitment and activity, ultimately impeding fungal clearance.