Head-to-head comparisons of Toxoplasma gondii and its near relative Hammondia hammondi reveal dramatic differences in the host response and effectors with species-specific functions.

Toxoplasma gondiiandHammondia hammondiare 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 similar to 95% the time, but the magnitude of the host response toH.hammondiwas significantly higher compared toT.gondii. Accompanying this divergent host response was an equally divergent impact on the cell cycle of the host cell. In contrast toT.gondii,H.hammondiinfection 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, priorT.gondiiinfection or treatment withT.gondii-conditioned media suppressed responses toH.hammondiinfection, and promoted the replication ofH.hammondiin recipient cells. Suppression of inflammatory responses toH.hammondiwas found to be mediated by theT.gondiieffector IST, and this finding was consistent with reduced functionality of theH.hammondiIST ortholog compared to itsT.gondiicounterpart. Taken together our data suggest thatT.gondiimanipulation of the host cell is capable of suppressing previously unknown stress and/or DNA-damage induced responses that occur during infection withH.hammondi, and that one important impact of thisT.gondiimediated suppression is to promote parasite replication. Author summary Humans can be infected withToxoplasma gondiifrom undercooked meat or exposure to feces from infected cats, and this parasite can cause lethal disease in those with HIV/AIDS, immunosuppressed organ transplant patients, and in the developing fetus.T.gondiiis a global parasite of all warm-blooded animals and has infected over a billion people worldwide, making it one of the more successful parasites on earth. To better understand whyT.gondiiis such a successful parasite, we have taken a comparative approach to investigate the role of the host response in determining infection outcome toT.gondiiand its nearest extant relative,Hammondia hammondi. These parasite species are closely related, sharing nearly all of their genes, butH.hammondiis not known to causes disease in humans and is highly avirulent in all animal models studied to date. Here we performed the first head-to-head comparison of the host response to these two parasite species and found a) thatH.hammondi-infected cells exhibited a more robust host response than those infected withT.gondiiand b) thatT.gondiican suppress host responses toH.hammondi. These studies not only implicate the acute host response as a mechanism for increased control ofH.hammondi in vivo, but also reveal previously unknown immune suppression mechanisms inT.gondii.