Mycobacterium tuberculosis Exploits Asparagine to Assimilate Nitrogen and Resist Acid Stress during Infection
| Autor: | Yannick Poquet, Roland Brosch, Alexia Dumas, Alexandre Gouzy, Florence Levillain, Dirk Schnappinger, Joshua B. Wallach, Olivier Neyrolles, Daria Bottai, Luiz Pedro S. de Carvalho, Chantal de Chastellier, Irène Caire-Brändli, Gerald Larrouy-Maumus, Ting-Di Wu, Jean-Luc Guerquin-Kern, Renaud Poincloux |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Vacuole
Mass Spectrometry Gene Knockout Techniques Mice chemistry.chemical_compound Phagosomes Asparagine Microscopy Immunoelectron lcsh:QH301-705.5 Phagosome 0303 health sciences Microscopy Confocal biology Flow Cytometry 3. Good health Host-Pathogen Interaction Biochemistry Female Mycobacterium tuberculosis Nitrogen Tuberculosis Research Article lcsh:Immunologic diseases. Allergy Asparaginase Phagosome acidification Immunoblotting Immunology Virulence Microbiology 03 medical and health sciences Stress Physiological Virology Genetics medicine Animals Biology Microbial Pathogens Molecular Biology Microbial Metabolism 030304 developmental biology 030306 microbiology Macrophages Membrane Transport Proteins biology.organism_classification medicine.disease Mice Inbred C57BL Disease Models Animal chemistry lcsh:Biology (General) Parasitology lcsh:RC581-607 Chromatography Liquid |
| Zdroj: | PLoS Pathogens, Vol 10, Iss 2, p e1003928 (2014) PLoS Pathogens PLoS Pathogens; Vol 10 |
| Popis: | 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. Author Summary Tuberculosis (TB) is still responsible for nearly 1.3 million deaths annually. There is an urgent need to identify novel drug targets in the tubercle bacillus, Mycobacterium tuberculosis, in order to develop novel therapeutics. To proliferate inside its human host, and ensure its spreading, M. tuberculosis must adapt its nutritional requirements and metabolism to the molecular environment it encounters during infection. Elucidating the origin, nature, and acquisition mechanisms of the nutrients required by M. tuberculosis inside its host may help identify targets for novel antimicrobials. In this study we asked how the TB bacillus acquires nitrogen, a vital constituent of all living organisms, from host tissues. We show the amino acid asparagine to be an important source of nitrogen for the bacillus, and we identify two bacterial proteins, AnsP2 and AnsA, that allow the pathogen to capture and ‘digest’ asparagine, respectively. In addition, we report that asparagine ‘digestion’ allows the pathogen to resist the host immune defense and to survive inside host cells and tissues. This study paves the way for future research into M. tuberculosis nitrogen metabolism, and for the development of alternative therapeutic strategies to impair nitrogen acquisition by the bacillus and treat patients with TB. |
| Databáze: | OpenAIRE |
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