Location: Animal Parasitic Diseases LaboratoryTitle: Parasite manipulation of the host cell cycle as a means to block inflammatory signaling and promote intracellular replication Author
|Wong, Zhee Sheen - University Of Pittsburgh|
|Sokol, Sarah - University Of Pittsburgh|
|Boyle, Jon - University Of Pittsburgh|
Submitted to: bioRxiv
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2019
Publication Date: 5/1/2019
Citation: Wong, Z., Sokol, S.L., Dubey, J.P., Boyle, J.P. 2019. Parasite manipulation of the host cell cycle as a means to block inflammatory signaling and promote intracellular replication. bioRxiv. https://doi.org/10.1101/625194
DOI: https://doi.org/10.1101/625194 Interpretive Summary: Toxoplasmosis, caused by the single celled parasite, Toxoplasma gondii, causes birth defects, mental retardation, and loss of vision in children and continues to be a public health concern worldwide. Approximately, one-third of humanity is infected with T. gondii but only a small proportion of population suffers clinically. The mechanism of disease process/host parasite interaction is not fully known. Scientists at the University of Pittsburgh in collaboration with a scientist from USDA have used a close relative of T. gondii, Hammondia hammondi to compare host interaction with these parasites; H. hammondi is non-pathogenic parasite. The results indicate that T. gondii is more successful in avoiding host defenses than H. hammondi. although cell cycles of these parasites are largely similar. These results will be of great interest to immunologists, cell biologists, and parasitologists.
Technical 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.