Mycobacterium bovis frd operon phase variation hijacks succinate signaling to drive immunometabolic rewiring and pathogenicity

Yuhui Dong, Xin Ge, Qingbin Guo, Xichao Ou, Chunfa Liu, Yuanzhi Wang, Ziyi Liu, Ruichao Yue, Weixing Fan, Yanlin Zhao () and Xiangmei Zhou ()
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Yuhui Dong: China Agricultural University
Xin Ge: China Agricultural University
Qingbin Guo: China Agricultural University
Xichao Ou: Chinese Center for Disease Control and Prevention
Chunfa Liu: Beijing University of Agriculture
Yuanzhi Wang: China Agricultural University
Ziyi Liu: China Agricultural University
Ruichao Yue: China Agricultural University
Weixing Fan: China Animal Health and Epidemiology Center
Yanlin Zhao: Chinese Center for Disease Control and Prevention
Xiangmei Zhou: China Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC) pathogens, remains a global health threat. While bacterial genetic adaptations during host infection 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. In macrophages, wild-type M. bovis secretes FRD-catalyzed succinate, stabilizing hypoxia-inducible factor-1α (HIF-1α) to drive glycolytic reprogramming and IL-1β production. This activates IL-1R-dependent Th1 immunity, restraining bacterial replication. Conversely, M. bovis frd HT insertion mutants impair succinate secretion, suppressing HIF-1α/IL-1β signaling and redirecting immunity toward pathogenic Th17 responses that promote neutrophil infiltration and tissue necrosis. Mice infection models reveal that M. bovis frd mutants exhibit enhanced pathogenicity, with higher pulmonary bacterial burdens. IL-1R blockade phenocopies frd HT insertion mutation effects, exacerbating lung pathology. Crucially, conserved frd HT polymorphisms in clinical M. tb isolates suggest shared immune evasion strategies across MTBC pathogens. Our work uncovers the bacterial gene phase variation mechanism of hijacking the succinate/HIF-1α/IL-1β axis to operate host immunity, providing a framework for targeting host metabolic checkpoints in TB therapy.

Date: 2025
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DOI: 10.1038/s41467-025-61824-9

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