Mycoplasma genitalium (MG) is an important reproductive tract pathogen associated with nongonoccocal urethritis (NGU), cervicitis, endometritis, pelvic inflammatory disease, preterm birth, and tubal factor infertility, and notable for its extremely reduced genome. MG is more prevalent than Neisseria gonorrhoeae in many settings and is a risk factor for HIV acquisition. MG may persist for months to years in infected individuals, increasing the risk of transmission and the potential for serious reproductive tract sequelae. These findings highlight the urgency of understanding the molecular pathogenesis of this novel pathogen while the emergence of antibiotic resistance and threat of untreatable strains of MG underscore the need to devise alternative prevention and treatment regimens for this underappreciated and underfunded pathogen. Over the past decade our laboratory has focused on the variability and antigenicity of two key proteins required for MG pathogenesis, the adhesins MgpB and MgpC. This research has demonstrated that MgpB and its accessory protein, MgpC, undergo phase and antigenic variation via a unique system of homologous reciprocal recombination between the mgpBC expression site and partial copies archived in the chromosome. Although MgpBC antigenic variation may allow MG persistence and re-infection, paradoxically the non-variable C- terminus contains both the adhesin domain and the dominant epitopes targeted by antibody-mediated complement killing. It is imperative to understand how MG persists in the face of a pronounced antibody response that targets a highly conserved region of the immunodominant adhesin. To this end, the experiments proposed will characterize the interactions between bacteria and host cell receptors, in addition to more accurately defining and comparing the epitopes within the C-terminus responsible for attachment and/or antibody-directed complement killing. This proposal utilizes an innovative combination of experimental techniques including Surface Plasmon Resonance to investigate the thermodynamics and kinetics of MgpB- receptor and MgpB-antibody interactions in experimentally infected/immunized animals and persistently infected men in addition to those techniques that have been historically successful in Mycoplasma research including hemadsorption, hemagglutination, and complement-mediated killing. The identification of biologically active immunogenic epitopes and the localization of functional domain(s) within the conserved C-terminus of MgpB are key to understanding the pathogenesis of MG infection. The data generated by this application, along with approaches that pioneer new experimental protocols in the difficult field of Mycoplasmology, will lead to future studies developing novel MG treatment and prevention strategies, including vaccines, to combat this increasingly antibiotic-resistant and important STD pathogen.

Public Health Relevance

The proposed studies will identify the targets of biologically active antibodies and adherence epitopes of the primary adhesin and immunogen of Mycoplasma genitalium (MG), a sexually transmitted bacterium recognized as a cause of reproductive (genital) tract disease in humans. These studies will help explain how MG persists in the reproductive tract despite a vigorous host immune response, and will lead to the identification of targets for vaccines to prevent infection and thus the sequelae of this increasingly antibiotic-resistant pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127981-02
Application #
9608705
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vincent, Leah Rebecca
Project Start
2017-12-06
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195