Population diversity in transcriptional responses of macrophages to TLR7/8 signaling (IRM12P.654)

Abstract

Abstract The Toll-like receptors (TLR) of the innate immune system play a key role in the recognition of pathogens and the initiation of a robust innate immune response. Although an innate immune response is essential for resistance to pathogen infection, the magnitude and qualities of innate immune responses are quite variable in the human population. Here we performed transcriptome sequencing of monocyte-derived macrophages generated from 78 healthy individuals, including 10 replicates from repeat donors, to profile gene expression patterns in responses to TLR7/8 signaling. Extensive qualitative and quantitative diversity was apparent in the response of individuals in this panel. Cluster analysis discriminated nine distinct clusters of genes expressed in response to the TLR7/8 agonist (R848) with correlated expression variations within this panel. Interestingly, the induction of cytokine and chemokine transcription varied among donors and majority of these genes have very reproducible variability of their expression in 10 replicates. In addition, it was shown that donors with high expression of cytokine and chemokine genes after R848 stimulation were also high responder to Respiratory syncytial virus infection. Thus, there are the variations in gene expression among individuals with TLR7/8 stimulation, indicating that genetic polymorphisms in “master” regulators may correlate expression patterns of multiple genes during innate responses.