Alternatively activated monocyte-derived myeloid cells promote extracellular pathogen persistence within pulmonary...

Area of Science:

• Immunology
• Mycology
• Infectious Diseases

Background:

• Inhaled fungal pathogens establish latent infections within granulomas, with potential for reactivation into invasive disease.
• Mechanisms preventing sterilizing immunity against latent fungal infections are not well understood.

Purpose of the Study:

• To investigate the immune dynamics and cellular architecture of cryptococcal granulomas during latent infection.
• To elucidate the role of T helper cells and myeloid cells in controlling or promoting fungal persistence.

Main Methods:

• Spatial transcriptomics and flow cytometry were employed to analyze granuloma composition.
• Fate mapping and murine genetic models were utilized to track immune cell function and interactions.
• Fungal localization within granulomas was assessed.

Main Results:

• Alternative activation of monocyte-derived myeloid cells by CD4+ T helper 2 cells was found to impede pulmonary fungal clearance.
• Contrary to previous beliefs, alternatively activated myeloid cells do not serve as a primary replication niche for the fungus.
• Cryptococcus was predominantly observed in the extracellular environment within granulomas.

Conclusions:

• A T helper 2 cell-myeloid cell circuit creates a local immunosuppressive environment, promoting extracellular fungal persistence.
• This circuit represents a potential therapeutic target for host-directed strategies against latent fungal infections.