Toxoplasma gondii-induced host cellular cell cycle dysregulation is linked to chromosome missegregation and cytokinesis failure in primary endothelial host cells

Anja Taubert,Zahady D. Velásquez,Carlos Hermosilla,Katharina Kerner,Camilo Larrazabal,Iván Conejeros

doi:10.1038/s41598-019-48961-0

Abstract

Toxoplasma gondii is a zoonotic and intracellular parasite with fast proliferating properties leading to rapid host cell lysis. T. gondii modulates its host cell on numerous functional levels. T. gondii was previously reported to influence host cellular cell cycle and to dampen host cell division. By using primary endothelial host cells, we show for the first time that T. gondii tachyzoite infections led to increased host cell proliferation and to an enhanced number of multi-nucleated host cells. As detected on DNA content level, parasite infections induced a G2/M cell cycle arrest without affecting expression of G2-specific cyclin B1. In line, parasite-driven impairment mainly concerned mitotic phase of host cells by propagating several functional alterations, such as chromosome segregation errors, mitotic spindle alteration and blockage of cytokinesis progression, with the latter most likely being mediated by the downregulation of the Aurora B kinase expression.

Highlights

Toxoplasma gondii is a globally occurring parasite which causes severe health problems in both, humans and animals
Given that mainly immortalized or tumor cell lines were used in the past in cell cycle-related studies on T. gondii infections, which may not reflect the actual situation within primary cells, and that recent data indicated cell type-specific reactions, we here aimed to analyze the impact of T. gondii tachyzoites on host cell cycle progression in primary endothelial cells, i.e. in a cell type that is infected by this parasite stage in vivo
Since T. gondii tachyzoite infections lead to enhanced host cell lysis from 24 h p. i. onwards in bovine umbilical vein endothelial cells (BUVEC), which obviously will falsify cell enumeration, the experiments were restricted to one day p. i

Summary

Introduction

Toxoplasma gondii is a globally occurring parasite which causes severe health problems in both, humans and animals. Some studies report that T. gondii infections cause diminished host cell proliferation and host cell cycle arrest[12,13,14]. The mitotic spindle promotes correct localization and migration of chromosomes in all mitosis steps This process is highly controlled and needs correct formation and localization of centrosomes to guide chromosomes to each cell pole of the cell. Given that mainly immortalized or tumor cell lines were used in the past in cell cycle-related studies on T. gondii infections, which may not reflect the actual situation within primary cells, and that recent data indicated cell type-specific reactions, we here aimed to analyze the impact of T. gondii tachyzoites on host cell cycle progression in primary endothelial cells, i.e. in a cell type that is infected by this parasite stage in vivo

Methods

Results

Conclusion