Chlamydia trachomatis (CT) infections are a major public health concern as they can adversely affect female fertility and neonatal health. While natural history studies indicate that some women spontaneously clear their infection, the physiological conditions that permit spontaneous clearance of CT remain elusive. Understand the latter is key to developing an effective vaccine that to prevent CT infection and its devastating consequences. In vitro and in vivo studies indicate that interferon gamma (IFN?) is the primary protective cytokine against CT. IFN? induces the host enzyme indoleamine 2,3-dioxygenase (IDO1) that degrades tryptophan, an essential amino acid for CT, which cannot synthesize tryptophan de novo. All clinical genital CT isolates have evolved a mechanism to evade the effect of IFN?, specifically they can express a functional tryptophan synthase that salvages exogenously provided indole to generate tryptophan within the intracellular chlamydial inclusion where it is impervious to IDO1. While neither CT, nor human cells, synthesize indole, some members of the vaginal microbiome that increase greatly in number and proportion during bacterial vaginosis (BV), can do so. Thus, we hypothesize that the composition of the vaginal microbiome, and its capacity to provide indole, modulates the efficacy of IFN?-dependent host immunity against CT. This hypothesis is supported by our existing clinical data; although all women who spontaneously cleared CT infection had high endocervical IFN? levels, so did ~40% of women who failed to clear infection. We propose to rigorously test this hypothesis using a cohort of high-risk African-American women attending our STD clinic in New Orleans. The cohort will be stratified into groups that spontaneously clear CT infections (~28% in our cohort) or fail to clear CT infection between enrollment and return-for-treatment visits. By focusing on women who spontaneously clear infection, and the ~40% of non- clearing women who meet the threshold endocervical IFN? levels observed in clearers, we will investigate the following objectives: 1) Determine the infection micromilieu (tryptophan/indole/IFN?/CT load & gene expression profile) correlates of clearance; 2) Determine differences in the prevalent vaginal microbiome, and its indole- generation capacity, between clearers and non-clearers; and 3) Using a novel endocervical epithelial cell model, directly test the capacity of indole-producing microbiome members to limit IFN?-mediated CT clearance, and evaluate the efficacy of known small molecule indole biosynthesis inhibitors to augment IFN?-mediated CT clearance during co-infections. The outcomes from the proposed studies will provide essential information needed to design novel immunological and pharmacological approaches that improve clinical outcomes for CT- infected patients. Modeling the mechanisms used during spontaneous clearance will define the effects of co- infection on the efficacy of the host response to CT-infection. This will significantly improve patient health and welfare in light of the tremendous human and financial toll that is imposed by genital CT infections.

Public Health Relevance

Co-infections with different sexually transmitted infections are common in the sexually active population. This study will determine how normal and abnormal co-infecting vaginal microbiota can interfere with the clearance of Chlamydia trachomatis infection by creating an environment that reduces the efficacy of the patient?s immune response against Chlamydia trachomatis, which is driven by the host cytokine interferon-gamma. New knowledge gained will provide key information necessary to prevent and treat the devastating effects of chronic and debilitating chlamydial infections on reproductive health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI118860-01A1
Application #
9240286
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Hiltke, Thomas J
Project Start
2017-08-08
Project End
2021-07-31
Budget Start
2017-08-08
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112