Functional characterization of Chlamydia trachomatis inclusion membrane proteins and their role in subversion of the host vesicular trafficking

University Of Iowa, Iowa City IA

Investigators

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Abstract

Project Summary Chlamydia trachomatis (C.t.) is the most common bacterial cause of sexually transmitted infections worldwide. Infections in women often go untreated due to subclinical inflammation masking symptoms, allowing the infection to persist and potentially leading to severe complications such as pelvic inflammatory disease, ectopic pregnancy, and infertility. Identifying and characterizing C.t. factors that drive pathogenesis and subvert host defenses is critical for developing effective therapeutics or vaccines. C.t. replicates within a specialized, host- derived vacuole called the inclusion, which is extensively modified by type III secreted effector proteins known as inclusion membrane (Incs) proteins. These Incs are essential for shielding the bacterium from immune detection and maintaining the inclusion as a replicative niche. Despite their importance, fundamental gaps remain in our understanding of how Incs coordinate interactions with host and bacterial factors to maintain inclusion integrity, prevent fusion with degradative compartments, and promote fusion with nutrient-rich vesicles. Our recent work has identified two key Inc proteins, CpoS and IncC, as critical for inclusion stability and bacterial replication. During the prior funding period, we demonstrated that CpoS forms a functional tetramer, engages multiple Inc proteins via its CC2 domain, and interacts with Rab GTPases through its CC1 domain. We hypothesize that CpoS and IncC coordinate a network of Inc-Inc and host interactions to construct and maintain a replicative niche that evades host immune defenses while supporting bacterial replication and nutrient acquisition. In Aim 1, we will determine how Rab-CpoS-Inc interactions mediate homotypic and heterotypic inclusion fusion, leveraging structural insights from Cryo-EM to evaluate how CpoS mimics SNARE proteins to drive membrane fusion. In Aim 2, we will elucidate how IncC disrupts host trafficking pathways to protect the inclusion from degradation and enable bacterial survival. This work will address critical questions in the field, advancing our understanding of C.t. pathogenesis and informing the development of innovative therapeutic strategies to combat persistent infections, ultimately reducing the global health burden associated with this pathogen.