Atherosclerosis has been associated with infection by the bacterial pathogen Chlamydia pneumoniae. The broad, long-term goal of the proposed studies is to define the mechanisms of C. pneumoniae pathogenesis that promote coronary artery disease. The research focus of this application is the molecular characterization of C. pneumoniae interactions with mammalian host cells during acute and persistent infection. The hypothesis is that C. pneumoniae produce components that elicit responses by the host cell and it is the consequent host cell responses including proinflammatory chemokines, growth factors and coagulation factors that mediate pathogenesis and arterial disease. The important role of persistent infection, characteristic of chlamydial infections, on cellular responses and staging the focal environment for chronic inflammation and consequent tissue damage will be evaluated. The significance of these studies is the identification of the cellular mediators of pathogenesis and the chlamydial products that elicit these responses thereby informing new approaches for control and diagnosis by identifying novel targets for diagnostic detection and vaccine or chemical intervention.
The specific aims will be investigated utilizing oligonucleotide and DNA array formats to measure changes in transcription in parallel for approximately 30,000 human genes and 1,100 C. pneumoniae genes. Human cellular responses will be tested in cells known to be infected by chlamydia in diseased arterial tissues including vascular endothelial cells, smooth muscle cells and macrophages.
The specific aims are: 1) Determine the spectrum of cellular responses to infection by C. pneumoniae. 2) Validate the protein expression of C. pneumoniae-induced changes in host cell gene transcription. 3) Characterize gene expression profiles for C. pneumoniae during persistent infection and during growth in different cell types. 4) Identify chlamydial products and test persistently-expressed C. pneumoniae gene products for their ability to induce host cell responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071730-02
Application #
6663824
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Tolunay, Eser
Project Start
2002-09-30
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$340,875
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Abromaitis, Stephanie; Stephens, Richard S (2009) Attachment and entry of Chlamydia have distinct requirements for host protein disulfide isomerase. PLoS Pathog 5:e1000357
Abromaitis, Stephanie; Hefty, P Scott; Stephens, Richard S (2009) Chlamydia pneumoniae encodes a functional aromatic amino acid hydroxylase. FEMS Immunol Med Microbiol 55:196-205
Buchholz, Kerry R; Stephens, Richard S (2008) The cytosolic pattern recognition receptor NOD1 induces inflammatory interleukin-8 during Chlamydia trachomatis infection. Infect Immun 76:3150-5
Kleba, Betsy; Stephens, Richard S (2008) Chlamydial effector proteins localized to the host cell cytoplasmic compartment. Infect Immun 76:4842-50
Buchholz, Kerry R; Stephens, Richard S (2007) The extracellular signal-regulated kinase/mitogen-activated protein kinase pathway induces the inflammatory factor interleukin-8 following Chlamydia trachomatis infection. Infect Immun 75:5924-9
Conant, Carolyn G; Stephens, Richard S (2007) Chlamydia attachment to mammalian cells requires protein disulfide isomerase. Cell Microbiol 9:222-32
Hybiske, Kevin; Stephens, Richard S (2007) Mechanisms of host cell exit by the intracellular bacterium Chlamydia. Proc Natl Acad Sci U S A 104:11430-5
Hybiske, Kevin; Stephens, Richard S (2007) Mechanisms of Chlamydia trachomatis entry into nonphagocytic cells. Infect Immun 75:3925-34
Fu, Zhu; Bettega, Kelly; Carroll, Susheela et al. (2007) Role of Ca2+ in responses of airway epithelia to Pseudomonas aeruginosa, flagellin, ATP, and thapsigargin. Am J Physiol Lung Cell Mol Physiol 292:L353-64
Buchholz, Kerry R; Stephens, Richard S (2006) Activation of the host cell proinflammatory interleukin-8 response by Chlamydia trachomatis. Cell Microbiol 8:1768-79