Parasite manipulation of the host cell cycle as a means to block inflammatory signaling and promote intracellular replication

Abstract

Toxoplasma gondii and Hammondia hammondi are closely-related coccidian intracellular parasites that differ in their ability to cause disease in animal and (likely) humans. The role of the host response in these phenotypic differences is not known and to address this we performed a transcriptomic analysis of a monocyte cell line (THP-1) infected with these two parasite species. The pathways altered by infection were shared between species ~95% the time, but the magnitude of the host response to H. hammondi was significantly higher compared to T. gondii. Accompanying this divergent host response was an equally divergent impact on the cell cycle of the host cell. In contrast to T. gondii, H. hammondi infection induces cell cycle arrest via pathways linked to DNA-damage responses and cellular senescence and robust secretion of multiple chemokines that are known to be a part of the senescence associated secretory phenotype (SASP). Remarkably T. gondii-conditioned media can suppress the SASP response during H. hammondi infection, and this suppression is accompanied by a corresponding increase in the replication rate of H. hammondi in recipient cells. Taken together our data suggest that T. gondii manipulation of the host cell cycle provides a novel mechanism to avoid stress and/or DNA-damage induced responses by the host cell, and that this ability has a direct impact on parasite replication rate both within the host cell as well as in bystander cells.