Vibrio cholerae O1 is the causative agent of pandemic cholera, a severe diarrheal disease still prevalent worldwide. The major etiologic agent of the Seventh Cholera Pandemic that began in 1961 and continues today is the cholera toxin producing El Tor O1 strains. These strains were first thought to have low virulence potential as they cause disease of less severity than """"""""classical"""""""" strain responsible for earlier pandemics. However, the lowered virulence of El Tor strains is believed to have contributed to their pandemic spread since a majority of infected persons do not become ill but do become colonized and excrete the infectious organisms. Indeed, one factor thought to contribute to the emergence of El Tor strains is their ability to persist an average of 5 days in asymptomatic carriers compared to only 1.5 days for classical strains. Thus, El Tor strains have genetic factor(s) absent in classical strains that contribute to prolonged colonization. These genetic factors had not been previously identified. Using a new animal model of cholera amenable to studies of the host immune response, we have demonstrated that accessory toxins hemolysin and RTX are key factors in establishment of prolonged V. cholerae colonization of the crypts of the small intestine. This grant will continue examining the connection between hemolysin, RTX and innate immunity using coinfection studies to determine if colonization defects can be extracellulary complemented. This study will also investigate the cell types recruited to the gut associated lymphoid tissue during early V. cholerae infection. Finally, this project will specifically determine whether neutrophils and mast cells are key components of the innate immune response to V. cholerae and whether these cells are disabled by hemolysin and RTX toxin both in vivo.

Public Health Relevance

Vibrio cholerae O1 is the causative agent of pandemic cholera, a severe diarrheal disease still prevalent worldwide. The epidemiology of modern cholera is distinct from the Classical disease as epidemics are caused by lower virulence strains that induce a high frequency of mild or asymptomatic infections. This prolonged period of vibrio excretion likely contributes to transmission of disease. Using a new animal model of cholera, accessory toxins hemolysin and RTX are shown to be key factors in prolonging intestinal colonization by V. cholerae. This project will investigate key components of the immune response to V. cholerae and identify is accessory toxins are associated with disabling innate immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21AI072461-02S1
Application #
8063715
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Hall, Robert H
Project Start
2010-05-01
Project End
2011-01-31
Budget Start
2010-05-01
Budget End
2011-01-31
Support Year
2
Fiscal Year
2010
Total Cost
$100,000
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
Queen, Jessica; Agarwal, Shivani; Dolores, Jazel S et al. (2015) Mechanisms of inflammasome activation by Vibrio cholerae secreted toxins vary with strain biotype. Infect Immun 83:2496-506
Queen, Jessica; Satchell, Karla J F (2013) Promotion of colonization and virulence by cholera toxin is dependent on neutrophils. Infect Immun 81:3338-45
Queen, Jessica; Satchell, Karla J Fullner (2012) Neutrophils are essential for containment of Vibrio cholerae to the intestine during the proinflammatory phase of infection. Infect Immun 80:2905-13
Jeong, Hee-Gon; Satchell, Karla J F (2012) Additive function of Vibrio vulnificus MARTX(Vv) and VvhA cytolysins promotes rapid growth and epithelial tissue necrosis during intestinal infection. PLoS Pathog 8:e1002581
Satchell, Karla J F (2011) Structure and function of MARTX toxins and other large repetitive RTX proteins. Annu Rev Microbiol 65:71-90
Kwak, Jayme S; Jeong, Hee-Gon; Satchell, Karla J F (2011) Vibrio vulnificus rtxA1 gene recombination generates toxin variants with altered potency during intestinal infection. Proc Natl Acad Sci U S A 108:1645-50
Egerer, Martina; Satchell, Karla J F (2010) Inositol hexakisphosphate-induced autoprocessing of large bacterial protein toxins. PLoS Pathog 6:e1000942
Satchell, Karla J F (2009) Actin Crosslinking Toxins of Gram-Negative Bacteria. Toxins (Basel) 1:123-133
Syed, Khalid Ali; Beyhan, Sinem; Correa, Nidia et al. (2009) The Vibrio cholerae flagellar regulatory hierarchy controls expression of virulence factors. J Bacteriol 191:6555-70
Olivier, Verena; Queen, Jessica; Satchell, Karla J F (2009) Successful small intestine colonization of adult mice by Vibrio cholerae requires ketamine anesthesia and accessory toxins. PLoS One 4:e7352