Transcription-based identification of uncharacterized genes in the human immune response.

Host-pathogen interactions are shaped by the nature of the pathogen and by host-related factors. Human host responses can be characterized in microbe-stimulated immune cells using transcriptomics. We set out to characterize gene expression changes as a result of microbial in vitro stimulation in medium-cultured human primary immune cells, using four pathogen ligands representing bacteria (LPS and S. aureus), viruses (Poly(I:C)) and fungi (C. albicans) for 4 and 24 h, resulting in a total of 52 samples for analysis. We analyze the transcriptional changes on gene and pathway levels, highlighting common and distinct effects of pathogen stimulation. We highlight genes without a known function that were differentially expressed as a common effect of pathogen stimulation. Amongst those, we find uncharacterized genes such as KIAA0040 and CYRIA to be co-expressed with genes involved in innate immunity and downstream signaling from the PRRs, respectively. Further linking our differential expression data to IEI, we identify 901 variants in uncharacterized genes in a cohort of patients with rare immune disorders, prioritizing 5 candidate variants in 4 genes that could underlie these diseases. Our results therefore indicate a potential role of these genes in the human immune response and provide further candidate variants for rare immune-mediated diseases.

© 2026. The Author(s), under exclusive licence to European Society of Human Genetics.

PMID: 42120540