Spontaneous preterm birth (PTB - <birth before 37 weeks gestation) is a major complication of pregnancy and infection is associated with ~ 50% of the cases. Although PTB has a multifactorial etiology, intraamniotic infection (IAI) and the resulting host (maternal and fetal) inflammatory response is a major component of the disease. Microbial factors are thought to evoke a series of events that compromise the immunological privileges that the fetus enjoys from conception until parturition by stimulating the production proinflammatory cytokines and chemokines that induce labor; however, the immune response is not generalizable. This suggests that initiation of labor may depend on the type of immune response to the type of pathogen. Other tissue and bacterial factor-specific cytokine response have also been reported. Not all cytokines, however, seem to activate the downstream mediators that cause labor and preterm birth suggesting that the biomolecular pathways from infection to preterm birth are complex and that patient-specific interventions targeted to a particular molecular mechanism of preterm birth may be necessary. Understanding the infectious etiology and pathophysiology of PTB is further complicated by disproportionately higher rate of infection and PTB rates in African-Americans than Caucasians. Racial differences in biomarker concentrations are expected to contribute to racial disparity. Furthermore, amniotic fluid consists of multiple antimicrobial factors and the concentration and regulatory mechanisms of these factors are also expected to differ in response to specific IAI and also in different races. Therefore, we hypothesize that host immune response and biochemical pathways of labor are not generalizable but differ between specific bacteria associated with IAI and race. In addition, we hypothesize that the immunomodulatory effects of amniotic fluid is also dependent on bacterial species and maternal race. We will test our hypotheses through the following specific aims;
Specific Aim 1 : To test the differences in the TH1/TH2 and proinflammatory cytokine/chemokine (IL-8) response and kinetics by normal human fetal membranes exposed to common intraamniotic pathogens including: Ureaplasma parvum, Mycoplasma hominis, E. coli, Group B Streptococcus, P. gingivalis and G. vaginalis.
Specific Aim 2 : To determine if there are racial differences in TH1/TH2 cytokine signature produced by fetal membranes in response to bacterial species listed above in Aim 1.
Specific Aim 3 : To test the anti-inflammatory properties of amniotic fluid in maintaining a balanced cytokine response.
Microbial invasion of the intraamniotic cavity and intraamniotic infections and inflammation mediated by a switch in the TH1/TH2 cytokine pattern favoring a proinflammatory response are commonly associated with spontaneous preterm birth. Disproportionately higher rate of infection and preterm births in African Americans and increasing rate of infection associated preterm birth suggest that the infection associated pathophysiologic pathways and biomarkers may not be generalizable and each bacterium may produce their own inflammatory signature and racial disparity will be associated with biomarker profile. In this RO3 application; a pilot study is planned using an in vitro organ explant system for fetal membranes we plan to test differential inflammatory response and racial disparity associated with common intraamniotic pathogens.
|Dixon, Christopher Luke; Richardson, Lauren; Sheller-Miller, Samantha et al. (2018) A distinct mechanism of senescence activation in amnion epithelial cells by infection, inflammation, and oxidative stress. Am J Reprod Immunol 79:|
|Menon, Ramkumar; Mesiano, Sam; Taylor, Robert N (2017) Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition. Front Endocrinol (Lausanne) 8:196|
|Bhat, Geeta; Peltier, Morgan R; Syed, Tariq Ali et al. (2013) Fetal membrane biomarker network diversity and disease functions induced by intra-amniotic pathogens. Am J Reprod Immunol 69:124-33|
|Abrahams, Vikki M; Potter, Julie A; Bhat, Geeta et al. (2013) Bacterial modulation of human fetal membrane Toll-like receptor expression. Am J Reprod Immunol 69:33-40|
|Peltier, Morgan R; Drobek, Cayce O; Bhat, Geeta et al. (2012) Amniotic fluid and maternal race influence responsiveness of fetal membranes to bacteria. J Reprod Immunol 96:68-78|