Stage conversion is a critical life cycle feature for several Apicomplexan parasites as the ability to switch between life forms is critical for replication, dissemination, pathogenesis and ultimately, transmission to a new host. In order for these developmental transitions to occur, the parasite must first sense changes in their environment, such as the presence of stressors or other environmental signals, and then respond to these signals by initiating global alterations in gene expression. As our understanding of the genetic components required for stage conversion continues to broaden, we can better understand the conserved mechanisms for this process and unique components and their contribution to pathogenesis by comparing stage conversion in multiple closely related species. In this review, we will discuss what is currently known about the mechanisms driving stage conversion in Toxoplasma gondii and its closest relatives Hammondia hammondi and Neospora caninum. Work by us and others has shown that these species have some important differences in the way that they (1) progress through their life cycle and (2) respond to stage conversion initiating stressors. To provide a specific example of species-specific complexities associated with stage conversion, we will discuss our recent published and unpublished work comparing stress responses in T. gondii and H. hammondi.

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, prior T. gondii infection or treatment with T. gondii-conditioned media suppressed responses to H. hammondi infection, and promoted the replication of H. hammondi in recipient cells. Suppression of inflammatory responses to H. hammondi was found to be mediated by the T. gondii effector IST, and this finding was consistent with reduced functionality of the H. hammondi IST ortholog compared to its T. gondii counterpart. Taken together our data suggest that T. gondii manipulation of the host cell is capable of suppressing previously unknown stress and/or DNA-damage induced responses that occur during infection with H. hammondi, and that one important impact of this T. gondii mediated suppression is to promote parasite replication.

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