Abstract

In immunocompromised and other severely ill patients, Pseudomonas aeruginosa (PA) causes an acute pneumonitis, which has an extremely high fatality rate. Improved methods for prevention and therapy are urgently needed. An in vitro model of PA infection using polarized Madin-Darby canine kidney (MDCK) cells or cultured lung epithelial cells mimics many important features of in vivo pneumonia. Live Pseudomonas organisms added to the apical surface of these cultures attach to and kill the cells. These foci of infection spread centripetally. The current proposal will study the host cell factors that determine susceptibility to Pseudomonas pneumonia using these in vitro model systems. There are four aims in this study: to investigate how modification of cell polarity affects virulence; to identify the receptors for PA and how their regulation affects bacterial interaction; to determine the pathway for internalization of PA organisms; and to examine the role of the actin cytoskeleton in interaction of PA with cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055980-07
Application #
6537251
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Colombini-Hatch, Sandra
Project Start
1995-09-30
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
7
Fiscal Year
2002
Total Cost
$239,574
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Kurahashi, Kiyoyasu; Sawa, Teiji; Ota, Maria et al. (2009) Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 296:L198-209
Kierbel, Arlinet; Gassama-Diagne, Ama; Rocha, Claudia et al. (2007) Pseudomonas aeruginosa exploits a PIP3-dependent pathway to transform apical into basolateral membrane. J Cell Biol 177:21-7
Kierbel, A; Gassama-Diagne, A; Mostov, K et al. (2005) The phosphoinositol-3-kinase-protein kinase B/Akt pathway is critical for Pseudomonas aeruginosa strain PAK internalization. Mol Biol Cell 16:2577-85
Kazmierczak, Barbara I; Mostov, Keith; Engel, Joanne N (2004) Epithelial cell polarity alters Rho-GTPase responses to Pseudomonas aeruginosa. Mol Biol Cell 15:411-9
Garrity-Ryan, L; Shafikhani, S; Balachandran, P et al. (2004) The ADP ribosyltransferase domain of Pseudomonas aeruginosa ExoT contributes to its biological activities. Infect Immun 72:546-58
Zegers, Mirjam M P; O'Brien, Lucy E; Yu, Wei et al. (2003) Epithelial polarity and tubulogenesis in vitro. Trends Cell Biol 13:169-76
McMorran, B; Town, L; Costelloe, E et al. (2003) Effector ExoU from the type III secretion system is an important modulator of gene expression in lung epithelial cells in response to Pseudomonas aeruginosa infection. Infect Immun 71:6035-44
Kazmierczak, B I; Jou, T S; Mostov, K et al. (2001) Rho GTPase activity modulates Pseudomonas aeruginosa internalization by epithelial cells. Cell Microbiol 3:85-98
Kazmierczak, B I; Mostov, K; Engel, J N (2001) Interaction of bacterial pathogens with polarized epithelium. Annu Rev Microbiol 55:407-35
Zhang, J R; Mostov, K E; Lamm, M E et al. (2000) The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102:827-37

Showing the most recent 10 out of 21 publications