Mobile genetic elements have profoundly influenced the evolution of bacterial pathogens. Many determinants of virulence and antibiotic resistance are borne by mobile elements, such as plasmids and bacteriophages, which are capable of horizontal transmission. During the current grant cycle, we explored several fundamental questions regarding the molecular biology of two mobile genetic elements, CTXqj and SXT, which have profoundly influenced the pathogenicity and evolution ofthe cholera pathogen. Vibrio cholerae. Addressing these aims has yielded observations that suggest previously unrecognized mechanisms of bacteriophage gene regulation and new insights regarding the biology and evolution of Integrative Conjugative Elements (ICEs). Furthermore, knowledge gained from these studies proved to be critical for our studies of the origin of the V. cholerae strain that gave rise to the cholera outbreak in Haiti. During this grant cycle, we also expanded the scope of our work to include investigation of new aspects of V. cholerae biology and pathogenicity. In particular, we developed a new infant rabbit model of disease that closely resembles human cholera. We will exploit this model and new high throughput tools we have developed to address three new aims during the MERIT extension period: 1) Assess the spatial and temporal patterns of V. cholerae gene expression during infection;2) Identify and characterize the determinants of V. cholerae transmission;and 3) Characterize the innate immune response to V. cholerae intestinal colonization. Completion of these studies will provide the most comprehensive knowledge ofthe course of gene expression during infection for any bacterial pathogen. Additionally, it will enhance our understanding of the processes underlying V. cholerae pathogenicity and transmission. Finally, these studies should provide insight into the innate immune response within the intestinal tract, modulation of which has profound ramifications both for normal intestinal homeostasis and for disease. Collectively, these studies will yield valuable new knowledge for the creation of new antimicrobial agents and vaccines.
threat from cholera, an acutely dehydrating diarrheal disease caused by Vibrio cholerae, is dramatically illustrated by the devesting cholera outbreak that began in Haiti in October 2010. The long-term aims of our studies - to understand the evolution, biology, and mechanisms of pathogenicity of V. cholerae - are promoting our ability to modulate disease in individuals and its spread within a community.
|Kimura, Satoshi; Hubbard, Troy P; Davis, Brigid M et al. (2016) The Nucleoid Binding Protein H-NS Biases Genome-Wide Transposon Insertion Landscapes. MBio 7:|
|Hatzios, Stavroula K; Abel, SÃ¶ren; Martell, Julianne et al. (2016) Chemoproteomic profiling of host and pathogen enzymes active in cholera. Nat Chem Biol 12:268-74|
|DÃ¶rr, Tobias; Alvarez, Laura; Delgado, Fernanda et al. (2016) A cell wall damage response mediated by a sensor kinase/response regulator pair enables beta-lactam tolerance. Proc Natl Acad Sci U S A 113:404-9|
|Sasabe, Jumpei; Miyoshi, Yurika; Rakoff-Nahoum, Seth et al. (2016) Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol 1:16125|
|Chao, Michael C; Abel, SÃ¶ren; Davis, Brigid M et al. (2016) The design and analysis of transposon insertion sequencing experiments. Nat Rev Microbiol 14:119-28|
|Hubbard, Troy P; Chao, Michael C; Abel, SÃ¶ren et al. (2016) Genetic analysis of Vibrio parahaemolyticus intestinal colonization. Proc Natl Acad Sci U S A 113:6283-8|
|DÃ¶rr, Tobias; Delgado, Fernanda; Umans, Benjamin D et al. (2016) A Transposon Screen Identifies Genetic Determinants of Vibrio cholerae Resistance to High-Molecular-Weight Antibiotics. Antimicrob Agents Chemother 60:4757-63|
|Blondel, Carlos J; Park, Joseph S; Hubbard, Troy P et al. (2016) CRISPR/Cas9 Screens Reveal Requirements for Host Cell Sulfation and Fucosylation in Bacterial Type III Secretion System-Mediated Cytotoxicity. Cell Host Microbe 20:226-37|
|Yamaichi, Yoshiharu; Chao, Michael C; Sasabe, Jumpei et al. (2015) High-resolution genetic analysis of the requirements for horizontal transmission of the ESBL plasmid from Escherichia coli O104:H4. Nucleic Acids Res 43:348-60|
|Osorio, Carlos R; Rivas, Amable J; Balado, Miguel et al. (2015) A Transmissible Plasmid-Borne Pathogenicity Island Confers Piscibactin Biosynthesis in the Fish Pathogen Photobacterium damselae subsp. piscicida. Appl Environ Microbiol 81:5867-79|
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