Campylobacter jejuni a NIAID Category B Priority Pathogen is a leading bacterial cause of human gastrointestinal disease worldwide. While the clinical presentation of C. jejuni infection is similar to Salmonella typhimurium, the virulence determinants and mechanisms that C. jejuni use to cause disease are unique. Our ultimate goal is to reduce the incidence and severity of C. jejuni infection. To accomplish this goal, we need a better understanding of the fundamental mechanisms of C. jejuni pathogenesis. We discovered that C. jejuni synthesizes at least two Microbial Surface Components Recognizing Adhesive Matrix Molecule(s) (MSCRAMM), designated CadF and FlpA, that promote the bacterium s binding to fibronectin. We have also discovered that maximal cell invasion requires the Campylobacter invasion antigens (Cia). The Cia proteins are defined as the proteins exported from the bacterium s flagellar Type III Secretion System (T3SS) that presumably modify host cell cytoskeletal regulatory proteins to promote C. jejuni-host cell entry and intracellular survival. However, significant gaps exist in our knowledge of the molecular mechanisms of C. jejuni binding and internalization. Based on our data and published papers, we hypothesize: 1) C. jejuni binds to fibronectin and stimulates outside-in signaling in epithelial cells that sets the stage for invasion by recruiting structural and signaling molecules to the sites of bacterial attachment; 2) C. jejuni Cia proteins exported from the flagellar export apparatus are delivered to the cytoplasm of host cells; and 3) C. jejuni Cia proteins stabilize or modify cellular structural components and signaling pathways to promote host cell entry and intracellular survival. The novelty of this proposal is that C. jejuni binding and invasion factors work cooperatively and simultaneously to modify host cell pathways, which when dissected completely will offer multiple targets for therapeutic intervention. The experiments outlined in this proposal are possible because we have the expertise to perform a variety of in vitro and in vivo assays and well-characterized C. jejuni mutants deficient in binding (e.g., cadF and flpA mutants), invasion (e.g., ciaB and ciaC mutants), and host cell survival (e.g., ciaI mutant). This study will result in the identification of novel C. jejuni virulence factors, and how these factors alter host cell signaling pathways to promote host cell invasion.

Public Health Relevance

An emerging theme among disease-causing bacteria is their ability to modify host cell behavior to cause disease. The purpose of this proposal is to dissect the multifactorial processes of C. jejuni binding and invasion of host cells in order to identify new targets for therapeutic intervention. The potential impact of our research is enormous given the number of food-borne illnesses caused by bacterial pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Ranallo, Ryan
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Washington State University
Schools of Arts and Sciences
United States
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O'Loughlin, Jason L; Samuelson, Derrick R; Braundmeier-Fleming, Andrea G et al. (2015) The Intestinal Microbiota Influences Campylobacter jejuni Colonization and Extraintestinal Dissemination in Mice. Appl Environ Microbiol 81:4642-50
O'Loughlin, Jason L; Eucker, Tyson P; Chavez, Juan D et al. (2015) Analysis of the Campylobacter jejuni genome by SMRT DNA sequencing identifies restriction-modification motifs. PLoS One 10:e0118533
Eucker, Tyson P; Samuelson, Derrick R; Hunzicker-Dunn, Mary et al. (2014) The focal complex of epithelial cells provides a signalling platform for interleukin-8 induction in response to bacterial pathogens. Cell Microbiol 16:1441-55
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Konkel, Michael E; Samuelson, Derrick R; Eucker, Tyson P et al. (2013) Invasion of epithelial cells by Campylobacter jejuni is independent of caveolae. Cell Commun Signal 11:100
Lu, Xiaonan; Samuelson, Derrick R; Xu, Yuhao et al. (2013) Detecting and tracking nosocomial methicillin-resistant Staphylococcus aureus using a microfluidic SERS biosensor. Anal Chem 85:2320-7
Lu, Xiaonan; Huang, Qian; Miller, William G et al. (2012) Comprehensive detection and discrimination of Campylobacter species by use of confocal micro-Raman spectroscopy and multilocus sequence typing. J Clin Microbiol 50:2932-46
Neal-McKinney, Jason M; Konkel, Michael E (2012) The Campylobacter jejuni CiaC virulence protein is secreted from the flagellum and delivered to the cytosol of host cells. Front Cell Infect Microbiol 2:31
Lu, Xiaonan; Samuelson, Derrick R; Rasco, Barbara A et al. (2012) Antimicrobial effect of diallyl sulphide on Campylobacter jejuni biofilms. J Antimicrob Chemother 67:1915-26
Lu, X; Weakley, A T; Aston, D E et al. (2012) Examination of nanoparticle inactivation of Campylobacter jejuni biofilms using infrared and Raman spectroscopies. J Appl Microbiol 113:952-63

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