Abstract
AbstractIntracellular pathogens including Mycobacterium tuberculosis (Mtb) have evolved with strategies to uptake amino acids from host cells to fulfil their metabolic requirements. However, Mtb also possesses de novo biosynthesis pathways for all the amino acids. This raises a pertinent question- how does Mtb meet its histidine requirements within an in vivo infection setting? Here, we present a mechanism in which the host, by up-regulating its histidine catabolizing enzymes through interferon gamma (IFN-γ) mediated signalling, exerts an immune response directed at starving the bacillus of intracellular free histidine. However, the wild-type Mtb evades this host immune response by biosynthesizing histidine de novo, whereas a histidine auxotroph fails to multiply. Notably, in an IFN-γ−/− mouse model, the auxotroph exhibits a similar extent of virulence as that of the wild-type. The results augment the current understanding of host-Mtb interactions and highlight the essentiality of Mtb histidine biosynthesis for its pathogenesis.
Funder
Department of Biotechnology, Ministry of Science and Technology
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference95 articles.
1. AlMatar, M., Makky, E. A., Var, I., Kayar, B. & Köksal, F. Novel compounds targeting InhA for TB therapy. Pharmacol. Rep. 70, 217–226 (2018).
2. Velayati, A. A. et al. Totally drug-resistant tuberculosis strains: Evidence of adaptation at the cellular level. Eur. Respir. J. 34, 1202–1203 (2009).
3. Kimerling, M. E. et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int. J. Tuberc. Lung Dis. 3, 451–453 (1999).
4. Al-Younes, H. M., Gussmann, J., Braun, P. R., Brinkmann, V. & Meyer, T. F. Naturally occurring amino acids differentially influence the development of Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. J. Med. Microbiol. 55, 879–886 (2006).
5. Westrop, G. D. et al. Metabolomic analyses of Leishmania reveal multiple species differences and large differences in Amino Acid Metabolism. PLoS ONE 10, 1–29 (2015).
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