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. 2025 Oct 28;44(10):116312.
doi: 10.1016/j.celrep.2025.116312. Epub 2025 Sep 16.

Innate immune molecular landscape following controlled human influenza virus infection

William Thistlethwaite  1 , Sindhu Vangeti  2 , Wan-Sze Cheng  3 , Pankaj Agarwal  4 , Antonio Cappuccio  3 , Wenliang Wang  5 , Bei Wei  6 , Rachel Myers  4 , Aliza B Rubenstein  3 , Daniel Chawla  7 , Manoj Hariharan  5 , Micah T McClain  4 , Thomas W Burke  4 , Steven H Kleinstein  8 , Joseph R Ecker  9 , Christopher W Woods  4 , William J Greenleaf  6 , Xi Chen  10 , Irene Ramos  11 , Elena Zaslavsky  3 , Thomas G Evans  12 , Olga G Troyanskaya  13 , Stuart C Sealfon  14
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Free article

Innate immune molecular landscape following controlled human influenza virus infection

William Thistlethwaite et al. Cell Rep. .
Free article

Abstract

Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find 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 find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Keywords: CP: Immunology; CP: Molecular biology; human challenge; influenza; innate immunity; multi-omics; scATAC-seq; scRNA-seq; transcriptomics.

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Conflict of interest statement

Declaration of interests T.G.E. is employed by Barinthus Biotherapeutics, the company that ran the clinical trial that provided the samples used in this study. An application for a patent based on the results from the single-nucleus methylation work has been filed with USPTO with the application nos. 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. This work was prepared while I.R. was employed at Icahn School of Medicine at Mount Sinai. The opinions expressed in this article are the author’s own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

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