: Chlamydia trachomatis infections are the most commonly reported transmissible diseases in the U.S. Diagnosis, treatment, and sequelae of chlamydial disease cost billions of dollars each year in the U.S. alone. The infection is often asymptomatic in women. Variations in the host immune response are likely to blame for adverse outcomes because not all persons who become infected will suffer the long-term consequences of the disease. In those who progress to disease, the affected tissues are significantly altered in their structure and function by a process that ultimately results in scarring and blockage of the fallopian tubes. This results in tubal factor infertility and risk of ectopic pregnancy. Our hypothesis is that those who sustain this outcome have dysregulation of factors which are responsible for the repair of the extracellular matrix. To address hypothesis, we will use a mouse model of chlamydial disease where inbred strains exist which have been characterized as resistant or susceptible as indicated by the outcomes of tubal damage and infertility. In approach, we will first extensively compare and contrast these strains with regard to their ability to modify and repair the extracellular matrix of the urogenital tract in vivo and in vitro. Subsequently, we will define the role of matrix metalloproteinases (MMPs) in the outcome of chlamydial disease through in vivo studies where the enzymes are inhibited pharmacologically or cytokines that influence their activity and production are neutralized. We will then define a role of specific metalloproteinases to the disease process through the use of mice with deletions in genes that encode the enzymes. Lastly, the contribution of specific inflammatory cells to the modulation of extracellular matrix in chlamydial disease will be defined by the production of bone marrow chimeras between susceptible and resistant strains of mice and subsequent depletions of leukocyte populations. In summary, it is the intent of this proposal to define host factors that are responsible for adverse chlamydial disease outcome. The information derived will assist in the development of therapies which could ameliorate the chlamydial disease process; noninvasive diagnostic indicators of progressive scarring and abnormal physiological outcome; development of prognostic indicators of those at high risk for chlamydial disease; and, further advances in design of a safe and effective chlamydial vaccine through avoidance of adverse outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049354-02
Application #
6624324
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Quackenbush, Robert L
Project Start
2002-03-01
Project End
2007-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
2
Fiscal Year
2003
Total Cost
$197,054
Indirect Cost
Name
Midwestern University
Department
Microbiology/Immun/Virology
Type
Schools of Osteopathy
DUNS #
181778846
City
Downers Grove
State
IL
Country
United States
Zip Code
60515
Lee, Hyo Y; Schripsema, Justin H; Sigar, Ira M et al. (2010) A link between neutrophils and chronic disease manifestations of Chlamydia muridarum urogenital infection of mice. FEMS Immunol Med Microbiol 59:108-16
Dixon, Rose Ellen; Ramsey, Kyle H; Schripsema, Justin H et al. (2010) Time-dependent disruption of oviduct pacemaker cells by Chlamydia infection in mice. Biol Reprod 83:244-53
Lee, Hyo Y; Schripsema, Justin H; Sigar, Ira M et al. (2010) A role for CXC chemokine receptor-2 in the pathogenesis of urogenital Chlamydia muridarum infection in mice. FEMS Immunol Med Microbiol 60:49-56
Dixon, Rose Ellen; Hwang, Sung Jin; Hennig, Grant W et al. (2009) Chlamydia infection causes loss of pacemaker cells and inhibits oocyte transport in the mouse oviduct. Biol Reprod 80:665-73
Ramsey, Kyle H; Sigar, Ira M; Schripsema, Justin H et al. (2009) Strain and virulence diversity in the mouse pathogen Chlamydia muridarum. Infect Immun 77:3284-93
Oberley, Rebecca E; Goss, Kelli L; Hoffmann, Darren S et al. (2007) Regulation of surfactant protein D in the mouse female reproductive tract in vivo. Mol Hum Reprod 13:863-8
Imtiaz, Muhammad T; Distelhorst, John T; Schripsema, Justin H et al. (2007) A role for matrix metalloproteinase-9 in pathogenesis of urogenital Chlamydia muridarum infection in mice. Microbes Infect 9:1561-6
Imtiaz, Muhammad T; Schripsema, Justin H; Sigar, Ira M et al. (2006) Inhibition of matrix metalloproteinases protects mice from ascending infection and chronic disease manifestations resulting from urogenital Chlamydia muridarum infection. Infect Immun 74:5513-21
Imtiaz, Muhammad T; Schripsema, Justin H; Sigar, Ira M et al. (2006) Outcome of urogenital infection with Chlamydia muridarum in CD14 gene knockout mice. BMC Infect Dis 6:144
Ramsey, K H; Sigar, I M; Schripsema, J H et al. (2005) Expression of matrix metalloproteinases subsequent to urogenital Chlamydia muridarum infection of mice. Infect Immun 73:6962-73

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