Abstract:
:The ability of the tubercle bacillus to arrest phagosome maturation is considered one major mechanism that allows its survival within host macrophages. To identify mycobacterial genes involved in this process, we developed a high throughput phenotypic cell-based assay enabling individual sub-cellular analysis of over 11,000 Mycobacterium tuberculosis mutants. This very stringent assay makes use of fluorescent staining for intracellular acidic compartments, and automated confocal microscopy to quantitatively determine the intracellular localization of M. tuberculosis. We characterised the ten mutants that traffic most frequently into acidified compartments early after phagocytosis, suggesting that they had lost their ability to arrest phagosomal maturation. Molecular analysis of these mutants revealed mainly disruptions in genes involved in cell envelope biogenesis (fadD28), the ESX-1 secretion system (espL/Rv3880), molybdopterin biosynthesis (moaC1 and moaD1), as well as in genes from a novel locus, Rv1503c-Rv1506c. Most interestingly, the mutants in Rv1503c and Rv1506c were perturbed in the biosynthesis of acyltrehalose-containing glycolipids. Our results suggest that such glycolipids indeed play a critical role in the early intracellular fate of the tubercle bacillus. The unbiased approach developed here can be easily adapted for functional genomics study of intracellular pathogens, together with focused discovery of new anti-microbials.
journal_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Brodin P,Poquet Y,Levillain F,Peguillet I,Larrouy-Maumus G,Gilleron M,Ewann F,Christophe T,Fenistein D,Jang J,Jang MS,Park SJ,Rauzier J,Carralot JP,Shrimpton R,Genovesio A,Gonzalo-Asensio JA,Puzo G,Martin C,Brosch Rdoi
10.1371/journal.ppat.1001100subject
Has Abstractpub_date
2010-09-09 00:00:00pages
e1001100issue
9eissn
1553-7366issn
1553-7374journal_volume
6pub_type
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