Investigation of the role(s) chlamydial polymorphic membrane proteins (pmps) play during infection with c. Trachomatis

The National Institute of Allergy and Infectious Diseases (NIAID) awarded The University of Kentucky Research Foundation a Project Grant totaling $423,500 under the Allergy and Infectious Diseases Research program (CFDA 93.855) effective July 1, 2025, through June 30, 2027. This research project investigates the functional roles of chlamydial polymorphic membrane proteins (PMPs), specifically PMPI, during the infectious cycle of Chlamydia trachomatis. The research will delineate the specific functions of PMPI across different developmental stages of the pathogen, characterize protein-protein interactions between PMPI and eukaryotic or chlamydial partner molecules, and advance understanding of how these surface-exposed autotransporters contribute to bacterial adhesion and pathogenesis.

The project addresses a significant public health burden, as C. trachomatis represents the leading cause of bacterial sexually transmitted infections in the United States, with over 1.6 million infections reported to the CDC in 2022, and causes potentially sight-threatening ocular infections. By elucidating the mechanisms underlying chlamydial virulence factors, this basic science research supports the broader NIAID mission to advance biomedical knowledge of infectious diseases and inform development of therapeutic and preventive interventions.

Abstract

Chlamydia trachomatis is an obligate intracellular, gram-negative human pathogen causing a variety of acute as well as chronic diseases. This bacterium infects primarily epithelial cells of mucosal surfaces of the urogenital tract and the human eye. Chlamydia-mediated genital infections represent the leading cause of bacterial stds in the united states, with 1,649,716 infections reported to the CDC in 2022. Conversely, chlamydia-mediated ocular infections cause follicular conjunctivitis, which can result in scaring of the eyelid and blindness. C. Trachomatis is subdivided into 15 major serovariants based on antibody response of infected patients to the chlamydial porin, major outer membrane protein (momp). In addition to momp, sera obtained from chlamydia-infected individuals showed a significant reactivity to the surface exposed autotransporters, polymorphic membrane proteins (pmps). Although all nine, pmpa to pmpi of c. Trachomatis are immunogenic, pmpb, c, d, and i are the most prevalent. This family of proteins are chlamydial adhesins secreted by type v secretion system and represent potential virulence factors, yet their role during chlamydial pathogenesis is mostly still unknown. Our preliminary data indicate that pmpi may play a distinct role(s) in infectious elementary bodies than in replicating reticulate bodies. We show that the deletion of pmpi in c. Trachomatis resulted in an impaired initial infection with chlamydial elementary bodies, but a formation of smaller chlamydial inclusions and a reduced number of new infectious progeny was also observed. We propose to delineate the specific function(s) of pmpi during different stages of the chlamydial developmental cycle. Since pmps are predicted chlamydial adhesins, we also intend to identify and characterize either eukaryotic and/or chlamydial pmpi interacting partner(s) during infection with the microorganism. Furthermore, we propose to utilize the conditionally replicating PKW shuttle vector in targeting the entire PMP loci in order to determine whether individual pmps of each locus may assume similar or distinct function during attachment, invasion, and/or throughout the developmental cycle. Phenotypical analyses of ∆pmpabc, ∆pmpfe, and ∆pmpgh chlamydiae will be compared with WT and corresponding CIS- complemented strains. Phenotypical outcomes will also be tested with other chlamydial species and various human and murine cell cultures to identify possible species-specific and host- specific interactions.