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

Area of Science:

• Genetics
• Immunology
• Veterinary Science

Background:

• Indicine cattle possess superior resistance to Mycobacterium bovis infection compared to taurine breeds.
• The Cytochrome b-245 (CYBB) gene is implicated in susceptibility to Mycobacterium tuberculosis complex (MTBC) infections.

Purpose of the Study:

• To investigate the genetic basis of bovine tuberculosis (bTB) resilience in indicine cattle.
• To identify and characterize novel CYBB gene variants associated with enhanced resistance to MTBC.

Main Methods:

• Analysis of X-chromosomal sequences from 258 female cattle.
• Functional studies using murine macrophages to assess the impact of the CYBB L237M variant.
• Investigation of ferroptosis, glutathione synthesis, and NADPH oxidase complex stability.

Main Results:

• A divergent missense variant, L237M, was identified in the CYBB gene, prevalent in indicine populations.
• The CYBB L237M variant mitigates M. tuberculosis-induced ferroptosis by increasing glutathione synthesis and glutathione peroxidase 4 expression.
• The L237M substitution stabilizes the NADPH oxidase 2 (NOX2)-p22phox complex, enhancing phagosomal reactive oxygen species generation and bacterial clearance.

Conclusions:

• The CYBB L237M variant promotes intracellular MTBC elimination via ferroptosis suppression, contributing to indicine cattle's superior bTB resistance.
• X-chromosomal variation in CYBB drives innate immunity against mycobacterial infections, offering insights for cattle breeding and tuberculosis therapies.