Loss of PmpC in Chlamydia trachomatis leads to altered bacterial development and impaired recovery from IFNγ- and penicillin-induced stress.

Chlamydia trachomatis is an obligate intracellular pathogen that can reversibly halt replication and developmental transitions in response to immunological or pharmacological stress, a phenomenon linked to chlamydial persistence. Although polymorphic membrane proteins (Pmps) are known adhesins, their broader roles in other pathogenesis-relevant processes remain poorly understood. Here, we characterized a pmpC-null mutant generated by insertional mutagenesis and found that while PmpC is not essential for primary growth, it is required for the efficient transition from reticulate bodies to infectious elementary bodies during recovery from IFNγ- and penicillin-induced stress. High-resolution microscopy and temporal expression analysis revealed that PmpC localizes to the bacterial periphery throughout the developmental cycle and is released into the lumen of pathogen-containing vacuoles (inclusions), suggesting a role beyond bacterial attachment to host cells. The absence of PmpC leads to clustered bacterial distribution and reduced bacterial mobility within the inclusion. These defects correlate with delayed cellular invasion and impaired dissemination to adjacent host cells. Notably, the significance of PmpC in penicillin-induced persistence was validated using an ex vivo murine uterine horn model. Altogether, our findings reveal PmpC as a multifunctional virulence factor that mediates stress recovery, regulates bacterial distribution and dynamics within the inclusion, modulates early invasion and facilitates lateral spread, expanding its recognized role as an adhesin.IMPORTANCEChlamydia trachomatis is a leading cause of sexually transmitted infections and preventable blindness globally. A significant challenge in controlling chlamydial diseases is the ability of these bacteria to enter a reversibly non-replicating "persistent" state to survive immune pressure, nutritional stress, or antibiotic treatment. In this study, we identify the surface protein PmpC as a multifunctional factor required for bacterial recovery from IFNγ- and penicillin-induced stress, in both tissue culture and an ex vivo murine model of uterine infection. Furthermore, we found that PmpC modulates invasion and bacterial spatial distribution within the inclusion. These findings uncover novel roles for PmpC as a virulence factor in C. trachomatis infection.