Chlamydia trachomatis Infection Causes Mitotic Spindle Pole Defects Independently from its Effects on Centrosome Amplification

Abstract

Chlamydiae are gram negative, obligate intracellular bacteria, and Chlamydia trachomatis is the etiologic agent of the most commonly reported sexually transmitted disease in the United States. Chlamydiae undergo a biphasic life cycle that takes place inside a parasitophorous vacuole termed an inclusion. Chlamydial infections have been epidemiologically linked to cervical cancer in patients previously infected by human papillomavirus (HPV). The inclusion associates very closely with host cell centrosomes, and this association is dependent upon the host motor protein dynein. We have previously reported that this interaction induces supernumerary centrosomes in infected cells, leading to multipolar mitotic spindles and inhibiting accurate chromosome segregation. Our findings demonstrate that chlamydial infection causes mitotic spindle defects independently of its effect on centrosome amplification. We show that chlamydial infection increases centrosome spread and inhibits the spindle assembly checkpoint delay to disrupt centrosome clustering. These data suggest chlamydial infection exacerbates the consequences of centrosome amplification by inhibiting the cells’ ability to suppress the effects of these defects on mitotic spindle organization. We hypothesize that these combined effects on mitotic spindle architecture identifies a possible mechanism for Chlamydia as a cofactor in cervical cancer formation.

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

“…8 Similarly, in HeLa cells infected with Chlamydia trachomatis (a bacterium that promotes centrosome amplification, clustering inhibition, and possibly cervical cancer development), centrosome clustering is suppressed even though dynein remains spindle-localized. 102 Therefore, spindle localization of dynein is insufficient for centrosome clustering in the presence of griseofulvin or C. trachomatis. Altogether, these studies suggest heterogeneity in clustering mechanisms across species and between human cell types, both transformed and nontransformed.…”

“…In host cells, C. trachomatis forms an inclusion that associates closely with the host centrosome, induces centrosome amplification, and somehow inhibits the cell's clustering machinery. 102 Given the bacterium's controversial relationship with cervical cancer, 137 much may be gained by analyzing its impact on centrosome declustering.…”

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

“…12 Persistent infections have recently been linked to severe chronic inflammatory diseases and cancer. 13 C. trachomatis is a Gram-negative, obligate intracellular bacterium that is restricted to humans. It has developed diverse strategies to invade, survive and multiply within eukaryotic cells.…”

Fierce Competition between Toxoplasma and Chlamydia for Host Cell Structures in Dually Infected Cells

“…Another factor that may contribute to the stress-induced persistent state of C. trachomatis during coinfection may be the failure to associate with the host MTOC by the inclusion. Many studies report that C. trachomatis modifies the host cell cycle by selectively targeting different cellular pathways (10,60,61). Although a potential selective advantage for Chlamydia in recruiting host centrosomes has not been demonstrated, it is possible to speculate that by stalling host cell division before cytokinesis, the bacterium ensures for itself a stable and spacious environment, sufficient to sustain its developmental cycle.…”