Dependency on host vitamin B12 has shaped Mycobacterium tuberculosis Complex evolution

Area of Science:

• Microbiology
• Infectious Diseases
• Host-Pathogen Interactions

Background:

• Human and animal tuberculosis is caused by the Mycobacterium tuberculosis Complex (MTBC).
• MTBC has undergone genomic decay of cobalamin (vitamin B12) biosynthetic genes.
• Unlike environmental mycobacteria, MTBC strains lack endogenous vitamin B12 production but can uptake it exogenously.

Purpose of the Study:

• To investigate the role of cobalamin (vitamin B12) in Mycobacterium tuberculosis (Mtb) virulence.
• To explore the mechanism of host-pathogen cross-talk related to vitamin B12.
• To assess the impact of host vitamin B12 levels on Mtb infection outcomes.

Main Methods:

• Utilized a vitamin B12 anemic mouse model (immunocompromised and immunocompetent) infected with Mtb.
• Compared infection outcomes (survival, bacterial load) in B12 anemic versus non-anemic mice.
• Analyzed the vitamin B12-responsive transcriptome in MTBC strains, focusing on L-methionine synthesis genes (metE and metH).
• Generated Mtb deletion mutants for metE and metH to assess their virulence in different host B12 conditions.

Main Results:

• B12 anemic mice infected with Mtb showed improved survival and lower bacterial loads compared to non-anemic controls.
• No significant difference in infection outcomes was observed when using M. canettii (retains B12 biosynthesis) in B12 anemic versus non-anemic mice.
• Expression of metE (repressed by B12) and metH (requires B12 cofactor) was critical for L-methionine synthesis.
• Deletion of metE primarily attenuated Mtb in anemic mice, while metH inactivation attenuated Mtb exclusively in non-anemic controls.

Conclusions:

• Sub-physiological vitamin B12 levels in the host antagonize Mtb virulence.
• Host vitamin B12 status influences Mtb's reliance on specific metabolic pathways (metE vs. metH).
• Identified a novel host-pathogen cross-talk mechanism with potential implications for vitamin B12 deficient populations.