Vibrio vulnificus is a natural inhabitant of coastal waters, including the US Gulf. The bacterium causes rapid septicemia after consumption of contaminated seafood (especially raw oysters), predominantly in persons with liver dysfunction. Among food-bourne pathogens, V. vulnificus is most notable for its high rates of hospitalization and death. Indeed, V. vulnificus accounts for 1% of deaths from food-bourne illness despite causing only 0.003% of illnesses. Although infections are rare, the number of serious infections has been increasing in recent years, possibly due to global warming that has caused a rise in the number of days amenable to growth of V. vulnificus in coastal waters. Attempts by the FDA to protect consumers by implementation of post-harvest processing mandates met with significant resistance from the shellfish harvesting industry forcing the FDA to review its policies. Thus, the study of V. vulnificus pathogenesis has become a food safety and public policy priority. Recent studies establish that cytotoxicity of V. vulnificus is predominantly associated with a large Multifunctional-Autoprocessing RTX toxin (MARTXVv). In this study, we demonstrate that this toxin is directly linked to pathogenesis by the intragastric route of infection, although its targets in vivo and molecular mechanism of action remain unknown. We propose to study the role of the MARTXVv toxin in pathogenesis using in vivo, cell culture, and biochemical systems. The focus of the proposal will be mechanisms directly impacting disease due to consumption of contaminated food and identification and characterization of specific regions of the toxin linked to cell lysis and increased virulence potential.

Public Health Relevance

Vibrio vulnificus is a bacterium that inhabits the US Gulf and causes sepsis and necrotizing fasciitis (flesh- eating bacteria). This study of V. vulnificus pathogenesis will specifically characterize a factor secreted by the bacterium that is linked to disease after consumption of contaminated food (especially oysters). When completed, this study will define how this factor contributes to food bourne infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092825-03
Application #
8486384
Study Section
Special Emphasis Panel (ZRG1-IDM-T (02))
Program Officer
Hall, Robert H
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$358,375
Indirect Cost
$123,375
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kim, Byoung Sik; Satchell, Karla J F (2016) MARTX effector cross kingdom activation by Golgi-associated ADP-ribosylation factors. Cell Microbiol 18:1078-93
Antic, Irena; Biancucci, Marco; Zhu, Yueming et al. (2015) Site-specific processing of Ras and Rap1 Switch I by a MARTX toxin effector domain. Nat Commun 6:7396
Agarwal, Shivangi; Agarwal, Shivani; Biancucci, Marco et al. (2015) Induced autoprocessing of the cytopathic Makes caterpillars floppy-like effector domain of the Vibrio vulnificus MARTX toxin. Cell Microbiol 17:1494-509
Agarwal, Shivangi; Zhu, Yeuming; Gius, David R et al. (2015) The Makes Caterpillars Floppy (MCF)-Like Domain of Vibrio vulnificus Induces Mitochondrion-Mediated Apoptosis. Infect Immun 83:4392-403
Satchell, Karla J F (2015) Multifunctional-autoprocessing repeats-in-toxin (MARTX) Toxins of Vibrios. Microbiol Spectr 3:
Dolores, Jazel S; Agarwal, Shivani; Egerer, Martina et al. (2015) Vibrio cholerae MARTX toxin heterologous translocation of beta-lactamase and roles of individual effector domains on cytoskeleton dynamics. Mol Microbiol 95:590-604
Tyson, Gregory H; Halavaty, Andrei S; Kim, Hyunjin et al. (2015) A novel phosphatidylinositol 4,5-bisphosphate binding domain mediates plasma membrane localization of ExoU and other patatin-like phospholipases. J Biol Chem 290:2919-37
Kim, Byoung Sik; Gavin, Hannah E; Satchell, Karla J F (2015) Distinct roles of the repeat-containing regions and effector domains of the Vibrio vulnificus multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin. MBio 6:
Gavin, Hannah E; Satchell, Karla J F (2015) MARTX toxins as effector delivery platforms. Pathog Dis 73:ftv092
Agarwal, Shivani; Kim, Hyunjin; Chan, Robin B et al. (2015) Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity. Nat Commun 6:8745

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