Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum

Area of Science:

• Immunology
• Mycology
• Infectious Diseases

Background:

• Antibodies' role in Histoplasma capsulatum (Hc) host defense is largely unknown.
• Hc is a pathogenic fungus causing histoplasmosis, a significant global health concern.

Purpose of the Study:

• To investigate the protective potential of monoclonal antibodies (mAbs) against Hc infection.
• To identify the target antigen and elucidate the mechanism of mAb-mediated protection.

Main Methods:

• Generation of mouse mAbs against Hc yeast.
• Administration of mAbs prior to Hc infection in a murine model.
• Assessment of fungal burden, pulmonary inflammation, survival, cytokine levels (IL-4, IL-6, IFN-gamma), and phagocytosis assays.
• Identification of the mAb-binding antigen via Western blot and mass spectrometry.

Main Results:

• Pre-infection mAb administration significantly reduced fungal burden, pulmonary inflammation, and prolonged survival.
• mAb treatment correlated with increased IL-4, IL-6, and IFN-gamma in infected lungs.
• mAbs enhanced phagocytosis of Hc yeast by macrophages via a CR3-dependent pathway.
• Ingestion of opsonized Hc led to growth inhibition and killing within macrophages.
• The target antigen was identified as a 17-kDa cell surface histone H2B-like protein.

Conclusions:

• Monoclonal antibodies targeting a specific Hc surface protein confer protection against lethal histoplasmosis in mice.
• Antibody-mediated protection involves enhanced phagocytosis, intracellular fungal killing, and modulation of the immune response.
• The identified histone H2B-like protein is a promising candidate antigen for Hc vaccine development.