How a cow TB bacterium rewires immune cells’ DNA activity

Bovine tuberculosis (bTB) is a chronic disease mainly caused by Mycobacterium bovis that damages livestock health and the global farming economy and can also infect other mammals, including humans. The bacterium first encounters and lives inside alveolar macrophages, the lung cells that normally swallow and destroy germs. Despite their importance, we still lack a clear picture of how these host cells and the pathogen interact at the genetic and epigenetic level — the layers of regulation that switch genes on and off without changing DNA sequence. To tackle that gap, a team led by corresponding author David E. MacHugh compared how bovine alveolar macrophages (bAM) respond when infected with live M. bovis and with related bacteria. The work compared M. bovis to M. tuberculosis (the main cause of human TB), the vaccine strain M. bovis BCG, and gamma-irradiated (killed) M. bovis. By looking across multiple molecular layers in the same system, the researchers set out to map the changes in gene activity and chromatin — the packaging of DNA that controls access to genes — that follow infection.

The study used a multi-omics approach that combined RNA-seq to measure gene expression with chromatin-focused tools ChIP-seq and ATAC-seq to map histone modifications and chromatin accessibility, respectively. Comparing these data sets revealed coordinated remodelling of chromatin accessibility and histone modification landscapes that underlies transcriptional activation of key immune and metabolic pathways in bAM after infection. Integrating the molecular profiles with a genome-wide association study (GWAS) for susceptibility to M. bovis infection highlighted specific candidate genes implicated in these regulatory networks, including ERBB4, LRCH1, MRTFA, and RNPC3. Importantly, the results show that M. bovis drives extensive reprogramming of the bAM epigenome in ways that are distinct from the responses elicited by other members of the M. tuberculosis complex (MTBC). Parallel experiments with M. tuberculosis, M. bovis BCG and gamma-irradiated M. bovis helped to distinguish responses tied to live M. bovis infection from those shared across related bacteria or caused by nonviable bacteria.

These findings matter because they point to a pathogen-driven mechanism by which M. bovis reshapes host immune cells to support its own survival. The multi-omics picture connects changes in chromatin and gene expression to genetic signals linked to disease susceptibility, suggesting that the identified regulatory networks are functionally relevant in natural infections. By naming specific genes and pathways involved in the macrophage response, the work offers molecular targets that could be used to develop new strategies to reduce bTB impact. One practical application the authors highlight is genome-enabled breeding: using genetic and regulatory information to select cattle with greater resilience to M. bovis. More broadly, the study shows how comparing related bacteria and combining RNA-seq, ChIP-seq, ATAC-seq and GWAS can reveal how pathogens reprogram host cells, which is a critical step toward interventions that protect animal health and limit zoonotic risk.