Methionine helps immune cells fight tuberculosis

Tuberculosis remains a global challenge because Mycobacterium tuberculosis (Mtb) can live inside immune cells called macrophages. New research led by Ranjan Kumar Nanda looks at how basic cell metabolism — specifically one-carbon metabolism — shapes the inflammatory response that clears Mtb. The team began by reanalyzing scRNAseq data from alveolar macrophages (AMs) taken from Mycobacterium tuberculosis H37Rv–infected C57BL/6 mice and found that two important players were suppressed: the enzyme PHGDH, which makes serine from a glycolytic intermediate, and the neutral amino acid transporter Slc7a5. PHGDH downregulation suggests that, when infected, these macrophages rely less on making serine internally and more on carbon from extracellular methionine to feed one-carbon reactions. At the same time, lower Slc7a5 expression pointed to reduced methionine uptake. To follow up, the researchers applied global metabolome analysis and proteome profiling to bone marrow-derived macrophages (BMDMs) infected with Mtb to trace how these shifts affect metabolites, proteins and the immune response over time.

Using global metabolome analysis of Mtb-infected BMDMs, the group observed a major biochemical shift at 24 hours post-infection (hpi). Metabolites linked to one-carbon metabolism were perturbed: intracellular serine, methionine and polyamine levels were significantly low, while adenine, hypoxanthine, guanine and reduced-glutathione (GSH) levels were high. These changes indicated that carbon units from one-carbon metabolism were being diverted toward nucleotide salvage and glutathione production at 24 hpi. Proteome profiling supported this, showing increased nucleotide salvage and glutathione production alongside a suppressed IL-1 response. Functionally, this metabolic rewiring correlated with a weaker immune response and poorer mycobacterial clearance. The team then tested methionine supplementation: adding methionine (1 mM) to BMDMs infected with Mtb improved cell viability, accelerated mycobacterial clearance and produced significantly higher IL-1β levels. In vivo, methionine given in drinking water to C57BL/6 mice for two weeks enhanced mycobacterial clearance in lungs and spleen and boosted pro-inflammatory signals, notably IL-1β and IFN-γ, and increased Mtb-specific TNF-α-producing activated CD4+ cells in the spleen.

Taken together, these findings show that Mtb infection decreases methionine uptake and serine synthesis in primary macrophages, redirecting one-carbon metabolism toward nucleotide salvage and glutathione at the expense of pro-inflammatory signaling. The reduction in IL-1 responses that accompanies this metabolic shift appears to let Mtb persist inside macrophages. Importantly, restoring methionine — both ex vivo in BMDMs and in vivo in C57BL/6 mice — helped restore a stronger acute pro-inflammatory response, increasing IL-1β, IFN-γ and TNF-α-producing CD4+ cells and improving bacterial clearance. The authors propose that simple dietary or supplemental methionine could be explored as a strategy to support the immune system during acute TB infection, by tuning metabolic pathways that control inflammatory cytokine production and microbial killing. These results, reported under the corresponding author Ranjan Kumar Nanda, point to metabolism as a modifiable lever for boosting host defense against Mtb and warrant further testing to assess safety and therapeutic value.