Vibrio vulnificus is a natural inhabitant of coastal waters, including the US Gulf. The bacterium causes severe life threatening infections after consumption of contaminated seafood (especially raw oysters) and from wounds contaminated by seawater. Among food-borne pathogens, V. vulnificus is most notable for its high rates of hospitalization and death and its negative economic impact. Indeed, V. vulnificus accounts for 72% of deaths from Vibrio illnesses despite causing only 13% of infections. Although infections are rare, the number of serious infections has been increasing globaly due to climate change that has caused a rise in the number of days amenable to growth of V. vulnificus in coastal waters and the geographical area amenable to the pathogen. Attempts by various agency to warn and protect citezens by implementation of new policies or issuing warnings have met with resistance for it effect on the shellfish harvesting industry and the tourist economy. Thus, the study of V. vulnificus pathogenesis has become both a food safety and public policy priority. A significant virulence factor of V. vulnificus is the large Multifunctional-Autoprocessing RTX toxin (MARTXVv). This toxin is comprised of long repeat regions that are associated with cellular necrosis, but this activity is not sufficient for virulence. Rather, virulence is associated with ?effector domains? that are translocated across host plasma membrane by repeat regions, and then released to the cell cytosol by inositol hexakisphophate induced autoprocessing. Bioinformatics studies reveal that different clinical isolates of V. vulnificus express distinct forms of the toxin, with five different variants assembled from eight different MARTX effector domains. To date, the mechanism of action of five of these domains has been determined. In this project, we will investigate the mechanism of action of the remaining effector domains found in clinical isolates. Further, we will study the relative toxicity of different variants of MARTXVv toxin in pathogenesis by the food- borne route of infection.

Public Health Relevance

Vibrio vulnificus causes highly lethal infections from eating shellfish, particularly oysters, or from swimming in warm seawater, including the US Gulf. Death can occur as fast as 24-48 hr after eating contaminated food or swimming. This project will define the biochemical process of how the major toxin produced by this bacterium destroys cells and how changes to the toxin can affect severity of food-bourne disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092825-07
Application #
9380956
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
2011-07-01
Project End
2021-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
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
Gavin, Hannah E; Beubier, Nike T; Satchell, Karla J F (2017) The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine. PLoS Pathog 13:e1006119
Biancucci, Marco; Dolores, Jazel S; Wong, Jennifer et al. (2017) New ligation independent cloning vectors for expression of recombinant proteins with a self-cleaving CPD/6xHis-tag. BMC Biotechnol 17:1
Gavin, Hannah E; Satchell, Karla J F (2017) Surface hypothermia predicts murine mortality in the intragastric Vibrio vulnificus infection model. BMC Microbiol 17:136
Biancucci, Marco; Rabideau, Amy E; Lu, Zeyu et al. (2017) Substrate Recognition of MARTX Ras/Rap1-Specific Endopeptidase. Biochemistry 56:2747-2757
Phillips, Kelsey E; Satchell, Karla J F (2017) Vibrio vulnificus: From Oyster Colonist to Human Pathogen. PLoS Pathog 13:e1006053
Kim, Byoung Sik; Gavin, Hannah E; Satchell, Karla J F (2017) Variable Virulence of Biotype 3 Vibrio vulnificus due to MARTX Toxin Effector Domain Composition. mSphere 2:
Song, Ha Yong; Biancucci, Marco; Kang, Hong-Jun et al. (2016) SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Oncotarget 7:80336-80349
Kim, Byoung Sik; Satchell, Karla J F (2016) MARTX effector cross kingdom activation by Golgi-associated ADP-ribosylation factors. Cell Microbiol 18:1078-93
Satchell, Karla J F (2015) Multifunctional-autoprocessing repeats-in-toxin (MARTX) Toxins of Vibrios. Microbiol Spectr 3:
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

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