The immune response influences the epigenomic landscape during infection by altering chromatin accessibility at immune regulatory genes. Cytomegalovirus (CMV), a member of the Herpesviridae family, establishes lifelong latency and can reactivate under favourable conditions (de Martino et al., 2019; Kua et al., 2023). Emerging evidence suggests that CMV may exacerbate susceptibility and activation of Mycobacterium tuberculosis (TB) infection (Olbrich et al., 2021), yet the underlying mechanisms remain poorly defined. Understanding these pathways is critical for developing therapeutic targets for TB prevention. Using ATAC-seq and mRNA-seq, we identified that murine CMV (MCMV) infection implicates T-cell activation pathways in early infection. Epigenomic profiling revealed increased chromatin accessibility in regions regulating suppressors and negative modulators of T-cell activation, supported by gene expression data. Initial responses appear protective against TB, favouring nitric oxide (NO) release and pro-inflammatory interferon-gamma (IFN-) signalling and Th1 polarisation. However, prolonged inflammation leads to immune exhaustion and increased vulnerability to TB reactivation. This immune modulation may contribute to chronic inflammation and impaired adaptive immune responses, facilitating TB activation. These findings have implications for addressing the rising global burden of TB, which affected 10.6 million individuals in 2021, with drug-resistant cases posing a growing challenge (World Health Organisation, 2022). Unravelling the interplay between CMV-induced immune modulation and TB susceptibility offers new avenues for therapeutic intervention.