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Published on: February 14, 2011
The genetic basis of variation in susceptibility to infection with Histoplasma capsulatum in the mouse
1Department of Molecular and Cell Biology, The University of California Berkeley, Berkeley, CA 94720-3202, USA.
Abstract:
The pathogenic fungus Histoplasma capsulatum causes disease ranging from mild to fatal in healthy and immunocompromised humans. Infection rates reach 80% in endemic areas, including the Midwestern United States. We used inbred mice to identify a 300-fold difference in fungal burden. A/J mice showed lower fungal burden and morbidity than C57BL/6J mice, a reversal of the trend observed for many bacterial pathogens. We mapped the differences in fungal burden to discrete locations on chromosomes 1, 6, 15 and 17 with high significance. Substitution of a single resistant chromosome 17 onto the susceptible background was sufficient to lower fungal burden. These loci will allow dissection of the fungal-specific immune program.
Insights
Genetic differences in mice reveal key immune responses to Histoplasma capsulatum infection. Researchers identified specific mouse chromosomes influencing fungal burden, offering insights into host-pathogen interactions.
Area of Science:
- * Medical Mycology and Immunology
- * Host-Pathogen Interactions
- * Genetic Susceptibility to Fungal Infections
Background:
- * Histoplasma capsulatum is a pathogenic fungus causing a spectrum of disease in humans, with high infection rates in endemic areas like the Midwestern US.
- * Understanding host genetic factors is crucial for managing histoplasmosis, particularly in diverse human populations.
- * Previous studies often show C57BL/6J mice as susceptible to pathogens, but this study investigates a different trend for fungal infections.
Purpose of the Study:
- * To identify host genetic loci controlling fungal burden and disease severity in experimental Histoplasma capsulatum infection.
- * To investigate the genetic basis for differential susceptibility between inbred mouse strains.
- * To lay the groundwork for dissecting the fungal-specific immune response.
Main Methods:
- * Utilized inbred mouse models (A/J and C57BL/6J) to assess differences in fungal burden and morbidity after H. capsulatum infection.
- * Employed quantitative trait loci (QTL) mapping to identify specific chromosomal regions associated with resistance or susceptibility.
- * Performed chromosome substitution experiments to validate the role of identified loci.
Main Results:
- * Identified a significant 300-fold difference in fungal burden between A/J and C57BL/6J mice, with A/J exhibiting lower burden and morbidity.
- * Mapped significant genetic loci associated with fungal burden to chromosomes 1, 6, 15, and 17.
- * Demonstrated that transferring a single resistant chromosome 17 segment to a susceptible background was sufficient to reduce fungal burden.
Conclusions:
- * Host genetic factors on specific chromosomes significantly influence susceptibility and fungal burden in Histoplasma capsulatum infections.
- * The identified genetic loci provide critical targets for further research into the host immune response against H. capsulatum.
- * This study highlights a unique genetic control of fungal pathogen burden, distinct from patterns observed with many bacterial pathogens.
