Innate Immune Epigenomic Landscape Following Controlled Human Influenza Virus Infection

Viral infections can induce changes in innate immunity that persist after virus clearance. Here, we used blood samples from a human influenza H3N2 challenge study to perform comprehensive multi-omic analyses. We detected remodeling of immune programs in innate immune cells after resolution of the infection that was proportional in magnitude to the level of prior viral load. We found changes associated with suppressed inflammation including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also found decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and epigenetic-remodeling showed modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the epigenetic landscape in innate immune cells induced by mild influenza virus infection. ### Competing Interest Statement T.G.E. is employed by Barinthus Biotherapeutics, the company that ran the clinical trial that provided the samples used in this study. Application for patent based on the results from the snMethylation work has been filed with USPTO with application number US 63/489,546 and PCT/US2024/019451. J.R.E. is a scientific advisor for Zymo Research Inc. and Ionis Pharmaceuticals. S.C.S. is interim Chief Scientific Officer, consultant, and equity owner of GNOMX Corp.