The objective of this project (2) is to characterize essential correlates of chlamydial infection of the human reproductive tract in the human reproductive tract. This will prime effective translational research through the identification and characterization of chlamydial antigens of relevance to vaccine development and of physiologic or pathogenetic mechanisms that are at play in the complex, natural environment of the female genital tract and provide targets for possible chemotherapeutic intervention. The project involves extensive collaboration with the complementary projects 1 and 3 of the CRC and will rely on Cores B, C and D for the provision of guinea pig and human sera and swabs, and biostatistical analysis of the results, respectively. In a first phase, the virulence of C. trachomatis and C. caviae genital isolates will be quantified in relationship to genome sequence type and reproductive tract ecology using a patient cohort representative of genital chlamydial disease in humans. Virulence will be measured using genomic doubling, infectious yield, inclusion fusogenicity and pathology as measurable physiological/pathogenic traits or endpoints, and using biomathematical modeling of Intracellular development and correlated pathology. A second phase of the research will be to investigate in relationship to genome sequence type and reproductive tract ecology the functional diversity of two gene families of C. trachomatis and C. caviae encoding inclusion membrane proteins (Inc) and effector proteins of the virulence-associated type III secretion (T3S) system that are targets for possible chemotherapeutic intervention. The developmental expression of selected inc and T3S effector genes in variants of C. trachomatis and C. caviae will be characterized and subcellular and molecular targets of variant Inc and T3S effector proteins will be identified. Finally, the diversity of the vaccine target pmp gene family and Pmp-specific antibody responses in C trachomatis -infected patients and C. caviae-infected guinea pigs will be investigated in relationship to genome sequence type and reproductive tract ecology. This will be achieved through characterization of the developmental expression of pmp genes in variants of C. trachomatis and C. caviae, profiling the high frequency on/off switching of Pmp expression in selected variants and performing cross-sectional and longitudinal investigations of the Pmp-specific antibody response comparatively in infected humans and guinea pigs.

Public Health Relevance

Chlamydial infection are a major health risk to young sexually active women and can results in serious conditions such as pelvic inflammatory disease (PID) a cause of infertility in women. Studies on Chlamydial infections have focused on the pathogen itself. It is becoming increasingly evident that the microbes that inhabit the vagina play a critical protective role. We will examine how the vaginal microbiota reacts to Chlamydial infections and treatments in order to provide a new view of the infectious process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI084044-05
Application #
8527684
Study Section
Special Emphasis Panel (ZAI1-MMT-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$433,796
Indirect Cost
$97,628
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Shannon, B; Yi, T J; Perusini, S et al. (2017) Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol 10:1310-1319
Tuddenham, Susan; Ghanem, Khalil G (2017) A microbiome variable in the HIV-prevention equation. Science 356:907-908
Oehlers, Stefan H; Flores, Maria Vega; Hall, Christopher J et al. (2017) A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation. FEBS J 284:402-413
Shannon, B; Gajer, P; Yi, T J et al. (2017) Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology. J Infect Dis 215:1366-1375
Smith, Steven B; Ravel, Jacques (2017) The vaginal microbiota, host defence and reproductive physiology. J Physiol 595:451-463
McClure, Erin E; Chávez, Adela S Oliva; Shaw, Dana K et al. (2017) Engineering of obligate intracellular bacteria: progress, challenges and paradigms. Nat Rev Microbiol 15:544-558
Dareng, E O; Ma, B; Famooto, A O et al. (2016) Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women. Epidemiol Infect 144:123-37
Ravel, Jacques; Brotman, Rebecca M (2016) Translating the vaginal microbiome: gaps and challenges. Genome Med 8:35
Van Lent, Sarah; De Vos, Winnok H; Huot Creasy, Heather et al. (2016) Analysis of Polymorphic Membrane Protein Expression in Cultured Cells Identifies PmpA and PmpH of Chlamydia psittaci as Candidate Factors in Pathogenesis and Immunity to Infection. PLoS One 11:e0162392
Nunn, Kenetta L; Forney, Larry J (2016) Unraveling the Dynamics of the Human Vaginal Microbiome. Yale J Biol Med 89:331-337

Showing the most recent 10 out of 42 publications