The Epigenetic Battleground: Host Chromatin at the Core of Infection

Chromatin dynamics are usually modulated by histone epigenetic post-translational modifications, which rapidly and reversibly govern accessibility and transcriptional responsiveness. During microbial infection, this regulatory layer becomes a highly contested interface where host defense mechanisms and pathogen-driven subversion strategies converge and compete. Many infectious agents exploit chromatin to reprogram gene expression, creating cellular environments that are conducive to infection, proliferation, and persistence. Diverse strategies have been described for viruses, bacteria, fungi, protozoa and nematodes, including the direct secretion of acetyltransferases and methyltransferases, interference with host chromatin-binding proteins, subcellular localization of transcriptional factors or epigenetic regulators, and metabolic availability manipulation. Concurrently, host cells activate immune and stress-response genes to mount rapid, adaptable antimicrobial responses. Recent advances in genome-wide, single-cell, and spatial omics profiling have begun to reveal the temporal and cell-type-specific dynamics of the host genome at the core of infection. This review synthesizes current insights into how chromatin is rewired by the major categories of pathogens during infection, highlighting representative case studies across infective agents and the functional consequences for immunity and cell fate. In addition, we discuss emerging techniques for epigenomic and transcriptomic data collection, and the potential of targeted host-directed therapeutic strategies. Chromatin regulation is thus a promising field of study and a possible target for next-generation interventions.