Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity.

Area of Science:

• Immunology
• Genetics
• Systems Biology

Background:

• Individual variations in innate immunity are influenced by host genetics and pathogen type.
• Monocytes play a crucial role in the innate immune response to diverse pathogens.

Purpose of the Study:

• To identify genetic factors (response quantitative trait loci or reQTLs) that explain interindividual differences in monocyte responses to fungal and bacterial pathogens.
• To characterize the pathogen-specific effects of these reQTLs on gene expression.

Main Methods:

• Analysis of quantitative trait loci (eQTLs) and transcriptomes from monocytes of 215 individuals.
• Stimulation of monocytes with fungal, Gram-negative, and Gram-positive bacterial pathogens.
• Identification and validation of reQTLs in male and female donors.

Main Results:

• Discovery of 745 reQTLs with pathogen-specific effects on gene expression, predominantly affecting upregulated genes.
• Identification of conserved monocyte responses to bacterial pathogens and a distinct antifungal response.
• reQTLs associated with key immune signaling pathways, including NOD-like, C-type lectin, Toll-like, and complement receptor signaling.

Conclusions:

• reQTLs provide a functional genetic basis for individual variation in innate immune responses to infection.
• The identified reQTLs are linked to diseases such as cancer, autoimmunity, and inflammatory/infectious conditions.
• These reQTLs represent candidate genes for understanding disease susceptibility and interindividual immune differences.