Contributors: Departamento de Microbiología, Medicina Preventiva y Salud Publica [Zaragoza]; Facultad de Medicina [Zaragoza]; Universidad de Zaragoza = University of Zaragoza [Saragossa University] = Université de Saragosse-Universidad de Zaragoza = University of Zaragoza [Saragossa University] = Université de Saragosse; Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES); Hospital Universitario Miguel Servet; Pathogénomique mycobactérienne intégrée; Institut Pasteur [Paris] (IP); This work was supported by the European Community's Framework Programme 7 grants NEWTBVAC 241745 and MM4TB 260872, the Spanish Ministry of Economy and Competitiveness grants BIO2011-23555 and FIS12/1970, the Fondation pour la Recherche Médicale FRM no. DEQ20130326471, and the Pyrenees biomedical network Refbio grant SecRegulTBC. Jesús Gonzalo-Asensio was supported by the Juan de la Cierva Programme (JCI-2009-03799) from the Spanish Ministry of Science and Innovation. Luis Solans was supported by grant BES-2009-013037.; We thank Marie-Agnès Dillies and Jean-Yves Coppée from the Transcriptome Platform PF2 at the Institut Pasteur for advice and Ida Rosenkrands from Statens Serum Institute for kindly providing the polyclonal anti-SigA antibodies, and we also gratefully acknowledge Alberto Cebollada for help with the sequence analysis of M. tuberculosis strains.; European Project: 241745,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,NEWTBVAC(2010); European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011); University of Zaragoza - Universidad de Zaragoza [Zaragoza]-University of Zaragoza - Universidad de Zaragoza [Zaragoza]; Institut Pasteur [Paris]
نبذة مختصرة : The ESX-1 secreted virulence factor ESAT-6 is one of the major and most well-studied virulence factors ofMycobacterium tuberculosis, given that its inactivation severely attenuates virulent mycobacteria. In this work, we show that clinical isolates ofM. tuberculosisproduce and secrete larger amounts of ESAT-6 than the widely usedM. tuberculosisH37Rv laboratory strain. A search for the genetic polymorphisms underlying this observation showed thatwhiB6(rv3862c), a gene upstream of the ESX-1 genetic locus that has not previously been found to be implicated in the regulation of the ESX-1 secretory apparatus, presents a unique single nucleotide insertion in its promoter region in strains H37Rv and H37Ra. This polymorphism is not present in any of the other publicly availableM. tuberculosiscomplex genomes or in any of the 76 clinicalM. tuberculosisisolates analyzed in our laboratory. We demonstrate that in consequence, the virulence master regulator PhoP downregulateswhiB6expression in H37Rv, while it upregulates its expression in clinical strains. Importantly, reintroduction of the wild-type (WT) copy ofwhiB6in H37Rv restored ESAT-6 production and secretion to the level of clinical strains. Hence, we provide clear evidence that inM. tuberculosis—with the exception of the H37Rv strain—ESX-1 expression is regulated by WhiB6 as part of the PhoP regulon, which adds another level of complexity to the regulation of ESAT-6 secretion with a potential role in virulence adaptation.
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