Doctor of Philosophy (PhD)
Pathology & Microbiology
Dr. Rey Carabeo
Chlamydia trachomatis is both the leading cause of non-congenital preventable blindness in developing nations and the leading source of bacterial sexually transmitted infections. As an obligate intracellular pathogen, Chlamydia has an absolute requirement on gaining entry into its host, which is accomplished by manipulating the host actin cytoskeleton to assemble engulfment structures that drive pathogen entry. In support of this, Chlamydia secretes the effectors TarP and TmeA via a type-III secretion system, whose respective signaling outputs operate synergistically to generate rapid actin kinetics and efficient pathogen engulfment. Rapid actin recruitment characteristic of invading Chlamydia is derived from a collaborative interaction between the actin nucleators formin and Arp2/3, which is established on the basis of signaling from both TarP and TmeA. Moreover, TarP signaling promotes the recruitment of focal adhesion proteins FAK, vinculin, Talin, and MPRIP, resulting in the assembly of a myosin-sensitive scaffold centered around TarP that accelerates both actin recruitment and turnover. Furthermore, our data provide preliminary support for the mechanical activation of TarP itself, representing the first known effector directly regulated by myosin II. The actin network generated by TarP and TmeA signaling drives the recruitment and activation of host dynamin-2, which catalyzes membrane scission of Chlamydia-containing vacuoles in support of rapid pathogen entry. Additionally, dynamin activity is co-regulated alongside actin turnover, implying a functional link between dynamin-dependent scission and actin depolymerization. Loss of either TarP or TmeA results in inefficient pathogen uptake, which is characterized by macropinocytotic uptake in TarP-deficient strains, and by deficiencies in both actin remodeling and dynamin 2 activation in TmeA-deficient strains. These data underscore the importance of TarP and TmeA synergy in coordinating successful invasion of host epithelial cells, an essential step of Chlamydia pathogenesis. Finally, we developed a robust method for tracking post-invasion maturation events, enabling high-throughput analysis of Chlamydia trafficking to correlate upstream perturbations of invasion-associated processes with their downstream impact on productive infection. In sum, our data exemplify the extraordinary control Chlamydia maintains over its invasion, utilizing signaling from both TarP and TmeA to manipulate a wide assortment of host processes that ensure efficient entry and productive infection.
Romero, Matthew, "Synergetic Signaling Between the Chlamydia Secreted Effectors TarP and TmeA Regulates Actin Kinetics and Efficient Entry" (2023). Theses & Dissertations. 789.
Available for download on Thursday, December 05, 2024