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

Innate immune responses vary by pathogen and host genetics. We generated transcriptomes of monocytes from 215 individuals, with and without stimulation (3h or 6h) by fungal, Gram-negative or Gram-positive bacterial pathogens. Monocytes showed a conserved response to bacterial pathogens and a distinct antifungal response. Mapping expression quantitative trait loci (eQTLs) identified 745 response eQTLs (reQTLs) and corresponding genes showing pathogen-specific effects. Compared to all differentially expressed genes, reQTL-regulated genes were more frequently upregulated, indicating cell-activating gene regulation. ReQTL-regulated gene products are essential in NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. ReQTLs functionally characterize risk variants identified through genome-wide association studies for autoimmunity, inflammatory or infectious diseases and cancer. Thus, in addition to the transcriptional response of monocytes, their genetic regulation differs for bacterial and fungal pathogens. ReQTLs help explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases. 3’-mRNA-sequencing of human monocytes from 215 healthy male blood donors after stimulation wit Aspergillus fumigatus, Neisseria meningitidis, Staphylococcus aureus or left unstimulated for 3h and 6h.