UC Berkeley

Toxoplasma gondii is an obligate intracellular protozoan parasite that infects a wide range of mammalian and avian hosts, including up to one third of the human population. Immunocompetent individuals clear acute infection with the parasite, however chronic infection is always established and persists for the life of the infected host. Reactivation of chronic infection in immunocompromised individuals, and vertical transmission from mother to fetus during acute infection can cause devastating neural pathology. Acute and chronic infection are associated with two distinct forms of the parasite: tachyzoites, which are fast replicating and responsible for acute infection and bradyzoites, which are slow replicating and establish chronic tissue cysts. During the course of infection, tachyzoites differentiate into bradyzoites. While tachyzoites can infect and replicate within virtually any nucleated cell, bradyzoite cysts typically only develop within neural and muscle tissue. Despite the critical importance of bradyzoite development to T. gondii pathogenesis, the factors responsible for this tissue tropism are unclear. Specifically, there are few defined molecular characteristics of the host cell that have been shown to regulate parasite growth and differentiation as bradyzoites.

Using an optimized in vitro system of bradyzoite induction, we have identified several new mechanisms by which T. gondii stage conversion is regulated in vitro. First, we have shown that enhancement of host cell glycolysis can support continued tachyzoite growth under metabolic stress conditions and thus inhibit bradyzoite conversion in a cell-intrinsic manner. Second, we have shown that cell lines that are intrinsically resistant to conversion, either basally or due to the induction of glycolysis, surprisingly release soluble mediators that inhibit conversion in trans. Finally, we have defined a new metabolic function for host Akt in T. gondii differentiation. These results suggest two new hypotheses as to how growth and differentiation of T. gondii may be regulated in vivo. One, the preferential encystment seen in highly glycolytic tissues may be a result of the ability of these tissues to sustain enhanced tachyzoite growth and increased parasite load, and if conversion from tachyzoites to bradyzoites is spontaneously occurring at some level in vivo, increased parasite load may lead to a higher incidence of cyst development in these tissues. Two, cells may broadly be releasing inhibitory mediators, making many tissues inhospitable to conversion, and thus restricting cyst development to particular tissues. While the in vivo significance of these hypotheses remains to be investigated, they provide a new metabolic framework within which the mechanisms that regulate tachyzoite to bradyzoite conversion in vivo can be investigated.