: Pertussis toxin is the major virulence factor of Bordetella pertussis. It is the most complex toxin known. Five different subunits associate in an unusual, 1:1:1:2:1 ratio. The subunits are secreted to the periplasm by the Sec-pathway where intramolecular disulfide bonds form and the subunits assemble into the functional toxin. Nine Ptl (for pertussis toxin liberation) proteins mediate secretion of properly assembled toxin past the outer membrane.
Specific Aim 1. Characterization of periplasmic folding and assembly of pertussis toxin. We have shown that disulfide bond formation occurs by an unusual pathway in Bordetella pertussis. The role of the novel periplasmic folding chaperones, and small thiols in the assembly of pertussis toxin will be investigated.
Specific Aim 2. The role of individual Ptl proteins in secretion. The function of the nine Ptl proteins will be investigated using genetic and biochemical methods with the goals of identifying the channel forming proteins, the glycohydrolase, proteins involved in assembly of the secretion complex, and proteins involved in specificity (e.g. distinguishing individual subunits from assembled pertussis toxin).
Specific Aim 3. Horizontal transfer of pertussis toxin genes. Two non-functional pertussis toxin operons (the chromosomal operon in Bordetella bronchiseptica, and the phage-encoded operon in Bordetella avium) will be investigated to gain an understanding of the unique events that occurred in the species B. pertussis that permit only them to express pertussis toxin. It is our hope that a detailed molecular understanding of the pertussis toxin secretion process will lead to better treatments for toxigenic diseases, including new therapeutics to block secretion, or """"""""anti-virulence"""""""" therapies that could be as effective as the current anti-microbial therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023695-19
Application #
6895578
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Lambert, Linda C
Project Start
1986-07-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
19
Fiscal Year
2005
Total Cost
$302,392
Indirect Cost
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Millen, Scott H; Watanabe, Mineo; Komatsu, Eiji et al. (2015) Single Amino Acid Polymorphisms of Pertussis Toxin Subunit S2 (PtxB) Affect Protein Function. PLoS One 10:e0137379
Schneider, Olivia D; Millen, Scott H; Weiss, Alison A et al. (2012) Mechanistic insight into pertussis toxin and lectin signaling using T cells engineered to express a CD8?/CD3? chimeric receptor. Biochemistry 51:4126-37
Komatsu, Eiji; Yamaguchi, Fuminori; Abe, Akio et al. (2010) Synergic effect of genotype changes in pertussis toxin and pertactin on adaptation to an acellular pertussis vaccine in the murine intranasal challenge model. Clin Vaccine Immunol 17:807-12
Millen, Scott H; Lewallen, Daniel M; Herr, Andrew B et al. (2010) Identification and characterization of the carbohydrate ligands recognized by pertussis toxin via a glycan microarray and surface plasmon resonance. Biochemistry 49:5954-67
Schneider, Olivia D; Weiss, Alison A; Miller, William E (2009) Pertussis toxin signals through the TCR to initiate cross-desensitization of the chemokine receptor CXCR4. J Immunol 182:5730-9
Schneider, Olivia D; Weiss, Alison A; Miller, William E (2007) Pertussis toxin utilizes proximal components of the T-cell receptor complex to initiate signal transduction events in T cells. Infect Immun 75:4040-9
Rambow-Larsen, Amy A; Weiss, Alison A (2004) Temporal expression of pertussis toxin and Ptl secretion proteins by Bordetella pertussis. J Bacteriol 186:43-50
Gamage, Shantini D; Strasser, Jane E; Chalk, Claudia L et al. (2003) Nonpathogenic Escherichia coli can contribute to the production of Shiga toxin. Infect Immun 71:3107-15
Stenson, Trevor H; Patton, Angela K; Weiss, Alison A (2003) Reduced glutathione is required for pertussis toxin secretion by Bordetella pertussis. Infect Immun 71:1316-20
Stenson, Trevor H; Weiss, Alison A (2002) DsbA and DsbC are required for secretion of pertussis toxin by Bordetella pertussis. Infect Immun 70:2297-303

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