Mycobacterium tuberculosis Exploits Asparagine to Assimilate Nitrogen and Resist Acid Stress during Infection

PLoS Pathogens

Alexia Dumas¹  Luiz Pedro Sório de Carvalho¹  Alexandre Gouzy¹  Irène Caire-Brandli¹  Renaud Poincloux²  Roland Brosch²  Ting-Di Wu³  Florence Levillain⁴  Dirk Schnappinger⁵  Jean-Luc Guerquin-Kern⁶  Olivier Neyrolles⁷  Daria Bottai⁸  Yannick Poquet⁹  Gérald Larrouy-Maumus⁹  Joshua B. Wallach⁹  Chantal de Chastellier⁹ 

[1] Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France;Centre d'Immunologie de Marseille-Luminy (CIML), Inserm UMR 1104, CNRS UMR 7280, Aix-Marseille University UM 2, Marseille, France;Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America;Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Pisa, Italy;INSERM U759, Orsay, France;Institut Curie, Laboratoire de Microscopie Ionique, Orsay, France;Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, Paris, France;Mycobacterial Research Division, MRC National Institute for Medical Research, London, United Kingdom;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France

关键词: Asparagine;    Mycobacterium tuberculosis;    Phagosomes;    Macrophages;    Ammonia;    Secretion systems;    Mutant strains;    Glutamate;   

DOI  :  10.1371/journal.ppat.1003928

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Mycobacterium tuberculosis is an intracellular pathogen. Within macrophages, M. tuberculosis thrives in a specialized membrane-bound vacuole, the phagosome, whose pH is slightly acidic, and where access to nutrients is limited. Understanding how the bacillus extracts and incorporates nutrients from its host may help develop novel strategies to combat tuberculosis. Here we show that M. tuberculosis employs the asparagine transporter AnsP2 and the secreted asparaginase AnsA to assimilate nitrogen and resist acid stress through asparagine hydrolysis and ammonia release. While the role of AnsP2 is partially spared by yet to be identified transporter(s), that of AnsA is crucial in both phagosome acidification arrest and intracellular replication, as an M. tuberculosis mutant lacking this asparaginase is ultimately attenuated in macrophages and in mice. Our study provides yet another example of the intimate link between physiology and virulence in the tubercle bacillus, and identifies a novel pathway to be targeted for therapeutic purposes.

【 授权许可】

CC BY