Chlamydia trachomatis Inclusions Induce Asymmetric Cleavage Furrow Formation and Ingression Failure in Host Cells

Abstract

Chlamydia trachomatis infection has been suggested to induce host genome duplication and is linked to increased risks of cervical cancer. We describe here the mechanism by which Chlamydia causes a cleavage furrow defect that consistently results in the formation of multinucleated host cells, a phenomenon linked to tumorigenesis. Host signaling proteins essential for cleavage furrow initiation, ingression, and stabilization are displaced from one of the prospective furrowing cortices after Chlamydia infection. This protein displacement leads to the formation of a unique asymmetrical, unilateral cleavage furrow in infected human cells. The asymmetrical distribution of signaling proteins is caused by the physical presence of the Chlamydia inclusion at the cell equator. By using ingested latex beads, we demonstrate that the presence of a large vacuole at the cell equator is sufficient to cause furrow ingression failure and can lead to multinucleation. Interestingly, internalized latex beads of similar size do not localize to the cell equator as efficiently as Chlamydia inclusions; moreover, inhibition of bacterial protein synthesis with antibiotic reduces the frequency at which Chlamydia localizes to the cell equator. Together, these results suggest that Chlamydia effectors are involved in strategic positioning of the inclusion during cell division.

Multinucleation during C. trachomatis Infections Is Caused by the Contribution of Two Effector Pathways

“…Sun et al demonstrated that steric effects of the chlamydial inclusion correlated with multinucleation [8]. Our data show that multinucleation is dependent on centrosome positioning defects, suggesting that the association between the chlamydial inclusion and the centrosomes can cause multinucleation at a low level without centrosome amplification, perhaps by causing steric interference with the centrosomes and the spindle apparatus during cell division.…”

Chlamydia trachomatis Inclusion Disrupts Host Cell Cytokinesis to Enhance Its Growth in Multinuclear Cells

“…We have previously demonstrated that C. trachomatis inclusions localize very efficiently to the host cell center during telophase using live imaging and IF in synchronized cells [Sun et al, ]. In the current study, we confirmed these observations with live cell DIC imaging in asynchronous cells.…”

“…Since Chlamydial protein synthesis played an important role in localizing the inclusion to the cell center to block host cell division [Sun et al, ], we next explored whether blocking host cell division conferred any physiological benefits to C. trachomatis . It has been well documented that the replicative success of C. trachomatis is highly dependent on access to host Golgi lipids [Heuer et al, ].…”

“…It has been well documented that C. trachomatis infection can lead to host cell multinucleation by disrupting host cytokinesis through disruption of furrow ingression or abscission [Greene and Zhong, ; Sun et al, ; Brown et al, ]. Moreover, a recent study has shown that C. muridarum can infect actively replicating host cells in a mouse model [Knowlton et al, ].…”

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…12 Chlamydia trachomatis was epidemiologically linked to increased risk of developing cervical cancer. 13 It affects genome stability by several mechanisms: multipolar spindle formation, 14,15 spindle assembly checkpoint override, 16 cytokinesis failure, 17,18 and induction of DNA damage coupled to impaired repair mechanisms. 19 The interplay between Lm and the host cell cycle is understudied.…”