Unknown,Transcriptomics,Genomics,Proteomics

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A Novel Gene Regulates Vesiculogenesis and Immunomodulation in Mycobacterium tuberculosis

ABSTRACT: After co-evolving with humans, its only major host, Mycobacterium tuberculosis (Mtb) restrains immune responses well enough to escape eradication, yet elicits enough immunopathology to ensure its transmission. Here, we provide evidence that this balance is regulated in part by a previously uncharacterized, cytosolic, membrane-associated protein with a novel structural fold, encoded by the Mtb gene rv0431. The protein acts by regulating the quantity and quality of Mtb-derived membrane vesicles bearing TLR2 ligands, including the lipoproteins LpqH and SodC. We propose that rv0431 be named virR (vesiculogenesis and immune response regulator). To our knowledge, VirR is the first bacterial protein identified to regulate vesiculogenesis. Transcriptome sequencing of mouse macrophages uninfected, infected with WT Mtb, or infected with rv0431 mutant Mtb.

ORGANISM(S): Mus musculus

SUBMITTER: Olivier Elemento

PROVIDER: E-GEOD-50050 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis.

Rath Poonam P Huang Chengdong C Wang Tao T Wang Tianzhi T Li Huilin H Prados-Rosales Rafael R Elemento Olivier O Casadevall Arturo A Nathan Carl F CF

Proceedings of the National Academy of Sciences of the United States of America 20131118 49

Mycobacterium tuberculosis (Mtb) restrains immune responses well enough to escape eradication but elicits enough immunopathology to ensure its transmission. Here we provide evidence that this host-pathogen relationship is regulated in part by a cytosolic, membrane-associated protein with a unique structural fold, encoded by the Mtb gene rv0431. The protein acts by regulating the quantity of Mtb-derived membrane vesicles bearing Toll-like receptor 2 ligands, including the lipoproteins LpqH and So ...[more]

PMID: 24248369

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Project description:Background: Conflicting results have been reported about the role of the two-component sensor and transcriptional regulator DosS/DosR, controlling the expression of the dormancy DosR regulon, for in vivo virulence of M. tuberculosis. Here, we have used a new approach to further analyze the relevance of the dosRS system, by driving DosR (Rv3133c) expression under the control of a constitutive promoter (phsp60). Methodology/Principal Findings: M. tuberculosis H37Rv constitutively expressing the transcriptional regulator DosR (Mtb::DosR) was compared to wild type M. tuberculosis (Mtb+/+) for in vitro growth kinetics and expression of the target genes of the DosR dormancy regulon, for in vivo virulence and for immunogenicity in mice. Under aerobic conditions, hsp60-driven DosR induced the expression of 28 out of 39 tested DosR regulon genes. In vitro growth characteristics were comparable for both strains, but Mtb::DosR showed an attenuated in vivo phenotype in immunocompetent mice, as indicated by reduced bacterial replication, reduced pulmonary immunopathology, reduced cachexia and significantly prolonged survival time as compared Mtb+/+. In immunodeficient SCID mice, Mtb::DosR was fully virulent. RT-qPCR analysis revealed a strong and comparable pulmonary TNF-?? and IL-23 expression following intratracheal infection, whereas IL-12 and IL-17 expression was slightly higher with wild type Mtb+/+. Finally, mice persistently infected with Mtb::DosR for 8 months showed five to tenfold higher lung IFN-?? responses against ten of the 48 DosR regulon encoded antigens (Rv1733c, Rv1734, Rv1738, Rv1996, Rv1997, Rv2029c, Rv2623, Rv2627c, Rv2628 and Rv3127) than mice actively infected with Mtb+/+. In spleen however, DosR regulon encoded antigen specific IFN-?? responses were similar in both groups. Conclusions/Significance. Collectively, these results suggest that increased DosR regulon encoded antigen specific pulmonary T cell responses are responsible for the attenuated phenotype of Mtb::DosR and that infection with Mtb::DosR could be used as a new animal model for studying key aspects of latent tuberculosis. Set of arrays that are part of repeated experiments

Dataset Information

A Novel Gene Regulates Vesiculogenesis and Immunomodulation in Mycobacterium tuberculosis

Publications

Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis.

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