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Phase variation in Mycobacterium bovis frd operon disrupts the succinate/HIF-1α/IL-1β axis to drive immunometabolic rewiring and enhance pathogenicity [RNA-seq]

ABSTRACT: Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC) pathogens, remains a global health threat. While bacterial genetic adaptations during host adaptation are poorly understood, phase variation in genomic homopolymeric tracts (HT) may drive pathogenicity evolution. Here, we demonstrate that M. bovis exploits HT insertion mutations in the fumarate reductase-encoding frd operon to subvert host immunometabolism. This study investigates the immunometabolic consequences of frd operon mutations in M. bovis-infected macrophages. RNA sequencing (RNA-seq) was performed on mouse bone marrow-derived macrophages (BMDMs) infected with wild-type M. bovis or its isogenic Δfrd mutant for 12 hours. Comparative transcriptomic analysis identified 192 upregulated and 344 downregulated genes in Δfrd-infected BMDMs, revealing significant suppression of innate immune pathways (e.g., defense response to Gram-positive bacteria, hypoxia adaptation) and upregulation of neutrophil chemotaxis/IL-17 signaling. Notably, Δfrd infection downregulated Gapdh (a glycolytic gatekeeper) and disrupted glucose metabolism-related pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE291007 | GEO | 2025/03/22

REPOSITORIES: GEO

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