Pathogens harbor virulence genes, which are required to cause disease. Paradoxically, pathogens also harbor anti-virulence genes, which restrict virulence potential. Anti- virulence genes likely play roles in chronic infection and transmission to new hosts. Understanding the interplay between virulence and anti-virulence genes will define the full range of variables that directly impact the progression of disease. This proposal seeks such understanding by focusing on the mgtCBR virulence operon of the facultative intracellular pathogen Salmonella enterica serovar Typhimurium, which specifies the F1Fo ATP synthase inhibitor MgtC, the Mg2+ transporter MgtB, and the MgtR peptide that promotes MgtC degradation. Homologs of the mgtC and/or mgtB genes are required for virulence in important human pathogens, including Mycobacterium tuberculosis, Burkholderia cenocepacia, Brucella suis, Yersinia pestis, Pseudomonas aeruginosa, and S. enterica serovars Typhi and Typhimurium. We propose to investigate how novel genetic elements control the temporal display of virulence, and how Salmonella regulates an anti-virulence trait. Specifically, we will explore the biochemical function and physiological role of two novel genes that modify the levels, activities and/or availability of the MgtC and MgtB virulence proteins. In addition, we will seek to understand how the structural protein MgtC enhances the levels of active PhoP, the master regulator of Salmonella virulence and transcriptional activator of the mgtC gene. Finally, we will explore the mgtCBR-mediated physiological changes that promote tolerance to antibiotics. The proposed research will reveal new concepts in bacterial pathogenesis applicable to various organisms and disease conditions.
| Yeom, Jinki; Gao, Xiaohui; Groisman, Eduardo A (2018) Reduction in adaptor amounts establishes degradation hierarchy among protease substrates. Proc Natl Acad Sci U S A 115:E4483-E4492 |
| Pontes, Mauricio H; Groisman, Eduardo A (2018) Protein synthesis controls phosphate homeostasis. Genes Dev 32:79-92 |
| Kriner, Michelle A; Groisman, Eduardo A (2017) RNA secondary structures regulate three steps of Rho-dependent transcription termination within a bacterial mRNA leader. Nucleic Acids Res 45:631-642 |
| Yeom, Jinki; Wayne, Kyle J; Groisman, Eduardo A (2017) Sequestration from Protease Adaptor Confers Differential Stability to Protease Substrate. Mol Cell 66:234-246.e5 |
| Pontes, Mauricio H; Yeom, Jinki; Groisman, Eduardo A (2016) Reducing Ribosome Biosynthesis Promotes Translation during Low Mg2+ Stress. Mol Cell 64:480-492 |
| Kriner, Michelle A; Sevostyanova, Anastasia; Groisman, Eduardo A (2016) Learning from the Leaders: Gene Regulation by the Transcription Termination Factor Rho. Trends Biochem Sci 41:690-699 |
| Park, Sun-Yang; Pontes, Mauricio H; Groisman, Eduardo A (2015) Flagella-independent surface motility in Salmonella enterica serovar Typhimurium. Proc Natl Acad Sci U S A 112:1850-5 |
| Kriner, Michelle A; Groisman, Eduardo A (2015) The Bacterial Transcription Termination Factor Rho Coordinates Mg(2+) Homeostasis with Translational Signals. J Mol Biol 427:3834-49 |
| Pontes, Mauricio H; Lee, Eun-Jin; Choi, Jeongjoon et al. (2015) Salmonella promotes virulence by repressing cellulose production. Proc Natl Acad Sci U S A 112:5183-8 |
| Sevostyanova, Anastasia; Groisman, Eduardo A (2015) An RNA motif advances transcription by preventing Rho-dependent termination. Proc Natl Acad Sci U S A 112:E6835-43 |
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