Long-Term Relationships: the Complicated Interplay between the Host and the Developmental Stages of Toxoplasma gondii during Acute and Chronic Infections

摘要

The development of tissue culture conditions that mimic bradyzoite formation in animals has greatly aided analyses of the asexual cycle. The transition from the rapidly replicating tachyzoite to the slow-growing bradyzoite is a stress response to immunological, metabolic, or chemical exposure. During such stresses, the growth of the parasite slows, bradyzoite-specific markers are expressed, and a cyst wall is formed. Many exogenous stresses independent of the host immune system contribute to tachyzoite-to-bradyzoite differentiation. Bradyzoite differentiation can be chemically induced in vitro through exposure to high pH (8.0 to 8.2), addition of sodium arsenite to culture medium, or shifting to higher temperatures (from 37C to 43C incubation) (26). These tissue culture conditions for bradyzoite development have greatly advanced the molecular analysis of the bradyzoite stage.The importance of IFN- is linked to its downstream effects, primarily through the stimulation of hundreds of genes in mice (79). These genes initiate a multitude of host responses necessary for control of the parasite, including immune cell proliferation, differentiation, and destruction of infected cells. Both hemopoietic and nonhemopoietic cells serve important roles during IFN--dependent host immunity to T. gondii infection (80). Guanylate-binding proteins (GBPs) and immunity-related GTPases (IRGs) are two major families of GTPases expressed in response to IFN- stimulation (81, 82). They are expressed in most cell types and aid in control of parasite replication by localizing to the parasitophorous vacuole (83, 84) (Fig. 4A). At the parasitophorous vacuole, IRGs disrupt the integrity of the membrane and cause release of the parasites into the host cell cytoplasm, where they are destroyed (85). While there are 23 different IRG genes in rodents, there are only two IRG genes present in humans (86). GBPs are expressed over a wide host range and, in response to T. gondii -induced IFN-, they localize to the parasitophorous vacuole (87, 88). GBPs help control parasite burden, but the exact mechanism of action is not understood. IFN- also controls parasite replication by cell-mediated nutrient starvation. T. gondii is an obligate intracellular parasite and relies on the host cell for multiple resources that it is unable to synthesize, such as tryptophan. IFN- induces indoleamine 2,3-dioxygenase production, an enzyme that converts tryptophan into an unusable form for the parasite and thus limits its growth (89, 90).