Genetic control of immune cell types in fungal disease

Area of Science:

• Immunology
• Genetics
• Mycology

Background:

• Latent infections by the fungus Histoplasma capsulatum are common, representing a complex interplay between host immunity and fungal virulence.
• Genetic background significantly influences host response and disease outcome in infectious diseases, as observed in different inbred mouse strains.

Purpose of the Study:

• To identify the genetic basis for differential susceptibility to Histoplasma capsulatum infection between inbred mouse strains.
• To elucidate the role of specific immune cell populations and gene expression patterns in determining histoplasmosis disease outcome.

Main Methods:

• Comparative analysis of Histoplasma capsulatum susceptibility across inbred mouse strains with varying MHC H2 loci.
• Gene expression profiling of immune cells to identify genotype-specific and independent signatures.
• Experimental manipulation of B cell and neutrophil populations to assess their impact on disease progression.

Main Results:

• A 250-fold difference in H. capsulatum susceptibility was mapped to the MHC H2 locus.
• Gene expression analysis revealed distinct immune signatures, including Clec7a, associated with infection and host genotype.
• B cell activity negatively correlated with fungal burden, while neutrophil activity correlated with improved disease outcome, a novel finding.

Conclusions:

• The MHC H2 locus genotype is a critical determinant of genetic susceptibility to histoplasmosis.
• Immune cell population dynamics, particularly the balance between B cells and neutrophils, profoundly influence histoplasmosis outcomes.
• Modulation of innate immunity offers a potential strategy for altering disease progression in fungal infections like histoplasmosis.