2. Academic Validation
  3. The Indicine X-linked CYBBL237M Mutation Can Suppress Intracellular Infection with Tubercle Bacilli

The Indicine X-linked CYBBL237M Mutation Can Suppress Intracellular Infection with Tubercle Bacilli

  • Genomics Proteomics Bioinformatics. 2025 Dec 23:qzaf131. doi: 10.1093/gpbjnl/qzaf131.
Haoxin Wang 1 2,  Xiaoting Xia 2,  Lulan Zeng 1 3,  Jing Yang 1,  Jing Han 1,  David E MacHugh 4 5,  Johannes A Lenstra 6,  Yanliang Song 1,  Ajiao Fan 1,  Yifan Zhu 7,  Zhenliang Zhu 1,  Xinyan Zhang 1,  Yingyu Chen 7,  Jianlin Han 2 8,  Chuzhao Lei 2,  Ningbo Chen 2,  Yong Zhang 1,  Yuanpeng Gao 1
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.
  • 2 Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
  • 3 College of Life Sciences, Northwest A&F University, Yangling 712100, China.
  • 4 College of Agriculture and Food Science, University College Dublin, Dublin D04 V1W8, Ireland.
  • 5 UCD One Health Centre, University College Dublin, Dublin D04 V1W8, Ireland.
  • 6 Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CM, The Netherlands.
  • 7 The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
  • 8 Yazhouwan National Laboratory, Sanya 572024, China.
PMID: 41433053 DOI: 10.1093/gpbjnl/qzaf131
Abstract

Indicine cattle exhibit superior resistance to Mycobacterium bovis Infection compared to taurine breeds, revealing divergent genetic mechanisms underlying bovine tuberculosis (bTB) resilience. Previous research has demonstrated that Cytochrome b-245 (CYBB) gene variants are associated with Mendelian susceptibility to Mycobacterium tuberculosis complex (MTBC) infections. In this study, we analyzed the X-chromosomal sequences from 258 female cattle and identified a divergent missense variant (L237M) in the CYBB gene. This variant occurs at high frequencies in indicine populations. Functional studies using murine macrophages revealed that CYBB L237M mitigates M. tuberculosis-induced Ferroptosis by elevating glutathione synthesis and Glutathione Peroxidase 4 expression. Mechanistically, the L237M substitution enhances the stability of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and p22phox complex (NOX2-p22), which is critical for the generation of phagosomal Reactive Oxygen Species and Bacterial clearance. Our findings demonstrate that CYBB L237M promotes intracellular MTBC elimination through Ferroptosis suppression, partially explaining the superior bTB resistance of indicine cattle. This study highlights X-chromosomal genetic variation as an evolutionary driver of innate immunity against mycobacterial infections, with implications for breeding strategies and host-directed tuberculosis therapies. The CYBB variant exemplifies how cattle subspecies divergence can illuminate conserved antimicrobial defense mechanisms in mammals.

Keywords

CYBB; Ferroptosis; NOX2–p22; Tuberculosis; X-chromosome.

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