R633
Publication Only
Clinical ID: Mycobacterial infections (including diagnosis)
Nitrogen metabolism and virulence in Mycobacterium tuberculosis
O. Neyrolles1
1Institute
of Pharmacology & Structural Biology, CNRS, Toulouse, France
Mycobacterium tuberculosis is a facultative 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 M. tuberculosis employs the aspartate transporter AnsP1, the asparagine transporter AnsP2 and
the secreted asparaginase AnsA to assimilate nitrogen and resist acid stress through aspartate and
asparagine catabolism and ammonia release1,2. A mutant in AnsP1 is severely impaired in mouse lung
colonization. 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 a 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 tuberculosis
bacillus, and identifies a novel pathways to be targeted for therapeutic purposes.
(1) Gouzy A, Larrouy-Maumus G, Bottai D, Levillain F, Dumas A, Wallach JB, Brandi I, de Chastellier C,
Wu TD, Poincloux R, Brosch R, Guerquin-Kern JL, Schnappinger D, de Carvalho LPS, Poquet Y & O
Neyrolles. Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress
during infection. PLOS Pathogens In revision
(2) Gouzy A, Larrouy-Maumus G, Wu TD, Peixoto A, Levillain F, Lugo-Villarino G, Guerquin-Kern JL, de
Carvalho LP, Poquet Y & Neyrolles O. 2013. Mycobacterium tuberculosis nitrogen assimilation and
host colonization require aspartate. Nature Chemical Biology 9:674-6