Nosocomial pneumonia is the second most common nosocomial infection and the leading cause of death from infection acquired in the hospital. P. aeruginosa is the most frequent gram negative bacteria involved in nosocomial pneumonia, and nosocomial pneumonias associated with P. aeruginosa infections have up to a 60% mortality despite appropriate antibiotic treatment. Also patients who are chronically infected with P. aeruginosa (i.e.: cystic fibrosis, HIV patients and bronchiectasis patients) become resistant to antibiotics and may die from their4 infections. Thus, there is an urgent need for novel treatments of P. aeruginosa infections. The long-term objectives of this grant are to determine the cell biology of a Pseudomonal protein, PcrV. PcrV is part of the bacterial type III secretory system; PcrV is involved in the translocation of bacterial toxins by P.aeruginosa into eukaryotic cells. It is also highly homologous to LcrV, a Yersinia protein also involved in the translocation. of that bacteria's toxins into eukaryotic cells. Antibodies to LcrV can protect animals from infections caused by Y. pestis and other Yersinia strains. Yet, although there are similarities between LcrV and PcrV, there are also important differences in the roles of LcrV compared to PcrV in the regulation of toxin secretion in the two strains. Therefore, PcrV warrants independent investigation. This group has shown that PcrV is accessible to antibody neutralization, that antibody attachment to PcrV blocks the translocation of the Pseudomonal toxins into eukaryotic cells and that antibody to PcrV protects animals infected with virulent P. aeruginosa from lung injury, sepsis and death. Therefore, therapies targeting PcrV appears clinically useful. Finally, many virulent gram negative bacteria utilize the type III secretory system which delivers bacterial toxins into eukaryotic cells. These gram negative bacteria, including enteropathic E. coli, Yersinia, Salmonella, produce bacterial proteins and structures similar to those found in P.aeruginosa. Therefore, understanding the mechanism of PcrV's role in bacterial translocation into eukaryotic cells may help in the development of other therapies targeting this widespread gram negative bacterial secretory system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044101-05
Application #
6725502
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Taylor, Christopher E,
Project Start
2000-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2006-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$313,175
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Moriyama, Kiyoshi; Wiener-Kronish, Jeanine P; Sawa, Teiji (2009) Protective effects of affinity-purified antibody and truncated vaccines against Pseudomonas aeruginosa V-antigen in neutropenic mice. Microbiol Immunol 53:587-94
Tamura, Miki; Ajayi, Temitayo; Allmond, Leonard R et al. (2004) Lysophospholipase A activity of Pseudomonas aeruginosa type III secretory toxin ExoU. Biochem Biophys Res Commun 316:323-31
Pankhaniya, Ravi R; Tamura, Miki; Allmond, Leonard R et al. (2004) Pseudomonas aeruginosa causes acute lung injury via the catalytic activity of the patatin-like phospholipase domain of ExoU. Crit Care Med 32:2293-9
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Faure, Karine; Sawa, Teiji; Ajayi, Temitayo et al. (2004) TLR4 signaling is essential for survival in acute lung injury induced by virulent Pseudomonas aeruginosa secreting type III secretory toxins. Respir Res 5:1
Allmond, Leonard R; Ajayi, Temitayo; Moriyama, Kiyoshi et al. (2004) V-antigen genotype and phenotype analyses of clinical isolates of Pseudomonas aeruginosa. J Clin Microbiol 42:3857-60
Faure, Karine; Shimabukuro, David; Ajayi, Temitayo et al. (2003) O-antigen serotypes and type III secretory toxins in clinical isolates of Pseudomonas aeruginosa. J Clin Microbiol 41:2158-60
Ajayi, Temitayo; Allmond, Leonard R; Sawa, Teiji et al. (2003) Single-nucleotide-polymorphism mapping of the Pseudomonas aeruginosa type III secretion toxins for development of a diagnostic multiplex PCR system. J Clin Microbiol 41:3526-31
Swanson, Britta; Savel, Richard; Szoka, Frank et al. (2003) Development of a high throughput Pseudomonas aeruginosa epithelial cell adhesion assay. J Microbiol Methods 52:361-6
Sato, Hiromi; Frank, Dara W; Hillard, Cecilia J et al. (2003) The mechanism of action of the Pseudomonas aeruginosa-encoded type III cytotoxin, ExoU. EMBO J 22:2959-69

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