Glutamate decarboxylase confers acid tolerance and enhances survival of mycobacteria within macrophages
Year: 2025
Type: article
Abstract: Host-induced metabolic adaptations are crucial for Mycobacterium tuberculosis (Mtb) survival and drug resistance. Mtb's persistence in the acidic environments of phagosomes and phagolysosomes suggests its initial metabolic adjustments respond to acidic stress. Glutamate decarboxylase (Gad) enzyme, converts glutamate to GABA while consuming a proton, helping regulate intracellular pH in bacteria. However, the role of Gad in mycobacteria has been unexplored. In this study, we investigated the function of Gad in Mtb and Mycobacterium smegmatis (MS), which are encoded by Rv3432c (gadB) and MSMEG_1574 (gadA), an ortholog of gadB, respectively. We observed upregulation of gad in both Mtb and MS under acidic stress and during infection within macrophages. Additionally, the expression of genes involved in glutamate metabolism and the GABA shunt, such as glutamine synthetase (glnA1), glutamate dehydrogenase (gdh), glutamate synthase (gltD/B), GABA-aminotransferase (gab-T), succinic semialdehyde dehydrogenase (gabD1/gabD2), α-ketoglutarate dehydrogenase (kdh), and 2-oxoglutarate dehydrogenase (sucA), were responsive to acidic conditions, reflecting a metabolic shift. Similar gene expression patterns were observed during macrophage infection. These findings suggest that Gad plays a role in mycobacterial acid stress response. To further elucidate this, we generated an MS gadA knockout strain (MSΔgadA) using allelic exchange. MSΔgadA exhibited reduced survival at pH 3.0, a phenotype rescued by gene complementation. MSΔgadA also showed decreased survival within macrophages. Additionally, Mycobacterium bovis BCG, which lacks native Gad expression, demonstrated enhanced intracellular survival when overexpressing Mtb gadB. These results suggest that Gad confers acid tolerance and promotes intracellular survival in mycobacteria, highlighting its potential role in host adaptation.
Source: Journal of Biological Chemistry
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: Arthritis National Research Foundation, Maulana Azad National Institute of Technology, Department of Biotechnology, Ministry of Science and Technology, India, Translational Health Science and Technology Institute, Albert Einstein College of Medicine, Yeshiva University, Science and Engineering Research Board, Arthur N. Rupe Foundation
OpenAlex ID: W4407836631