In Search of a Mechanistic Link between Chlamydia trachomatis-Induced Cellular Pathophysiology and Oncogenesis

Abstract

Centrosome duplication and cell cycle progression are essential cellular processes that must be tightly controlled to ensure cellular integrity. Despite their complex regulatory mechanisms, microbial pathogens have evolved sophisticated strategies to co-opt these processes to promote infection. While misregulation of these processes can greatly benefit the pathogen, the consequences to the host cell can be devastating. During infection, the obligate intracellular pathogen Chlamydia trachomatis induces gross cellular abnormalities, including supernumerary centrosomes, multipolar spindles, and defects in cytokinesis. While these observations were made over 15 years ago, identification of the bacterial factors responsible has been elusive due to the genetic intractability of Chlamydia. Recent advances in techniques of genetic manipulation now allows for the direct linking of bacterial virulence factors to manipulation of centrosome duplication and cell cycle progression. In this review, we discuss the impact, both immediate and downstream, of C. trachomatis infection on the host cell cycle regulatory apparatus and centrosome replication. We highlight links between C. trachomatis infection and cervical and ovarian cancers and speculate whether perturbations of the cell cycle and centrosome are sufficient to initiate cellular transformation. We also explore the biological mechanisms employed by Inc proteins and other secreted effector proteins implicated in the perturbation of these host cell pathways. Future work is needed to better understand the nuances of each effector's mechanism and their collective impact on Chlamydia's ability to induce host cellular abnormalities.

Keywords: Chlamydia; centrosomes; cervical cancer; ovarian cancer; secreted effector.

FIG 1

Centrosome structure. The centrosome is composed of two centrioles, a mature mother centriole and an immature daughter centriole. The mother centriole is distinct because it has distal and subdistal appendages. The centrioles are connected for part of the cell cycle by a protein linker and are surrounded by varying amounts of pericentriolar material, again dependent on the stage of replication. Each centriole consists of triplets of microtubules arranged around a central cartwheel structure with the conserved 9-fold symmetry. The centrosome is the site of microtubule nucleation.

FIG 2

Centrosome duplication and the cell cycle. Centrosome duplication is intricately linked to the cell cycle. At the start of G1, a mature mother centriole is connected to an immature daughter centriole by a linker protein. Numerous proteins are recruited to the site of duplication and initiate duplication through the formation of a procentriole structure on each the two centrioles. Procentrioles are elongated through S phase to become immature centrioles. In preparation for M phase, during G2, the previously immature daughter centriole matures and the protein linker between the new centrosomes degrades allowing one centrosome to migrate to each pole of the cell to orchestrate chromosomal segregation during mitosis.

FIG 3

Role of C. trachomatis secreted factors in manipulation of the centrosome. After the bacterium is internalized into a host cell, it survives in a membrane compartment that is extensively modified by incorporation of inclusion membrane proteins. Interactions between dynein and the Inc protein CT850 are believed to promote inclusion trafficking to the MTOC. Other Inc proteins, including CT288 and IPAM, bind to centrosomal components CCDC146 and CEP170, respectively. Dre1, through interactions with dynactin, relocalizes the centrosomes to the inclusion. The secreted factor CteG binds CETN2 to induce centrosome amplification. While CPAF also induces centrosome amplification, the host cell target is unknown. CT847 binds to and promotes degradation of GCIP potentially altering host cell cycle progression.