Toxoplasma gondii is a zoonotic protozoan that infects an estimated 1.5 million human subjects annually, and infection can be dangerous to the unborn, to patients undergoing chemotherapy or organ transplant, and to people with AIDS. Bradyzoite development is responsible for permanent infection and recrudescence to the lytic tachyzoite stage underlies the pathogenesis of clinical toxoplasmosis. The molecular basis for specific host-parasite interaction leading to bradyzoite development is mostly unknown, but evidence suggests that preferential development in long-lived, terminally differentiated cells like muscle and select cells of the brain can be dictated by the interaction of distinct, definable host- and parasite-specific factors. We have demonstrated treatment of the host cell with a trisubstituted pyrrole, designated Compound 1, induces new host cell gene expression and early bradyzoite development. One host mRNA expressed in the Compound 1-altered cell, called cell division autoantigen 1 (CDA1), is able to induce parasite development when over-expressed in the infected host cell alone. Our hypothesis is that increased CDA1 is one part of a molecular environment in the host that 'signals', or can be 'acted on' by, the parasite to initiate bradyzoite development. The molecular elements of this altered environment and the host- or parasite-specific molecules pertinent to induced development will have significant implications for understanding the pathogenesis of chronic Toxoplasma infection. To identify these key molecules and provide a basis for future experiments to understand the relevant interactions leading to natural bradyzoite development in the animal, we will (1) We will complete structure function studies to identify sequence elements in the CDA1 protein critical to induction of bradyzoite development and (2) identify the genetic elements that underlie parasite susceptibility to the Compound 1-altered host cell environment.
Toxoplasma is a common opportunistic pathogen in AIDS. We have found the parasite can take cues from the host cell to establish permanent infection. These studies will seek to characterize the host cell influence on development using both host- and parasite-specific approaches to understand key molecular interactions that influence the pathogenesis of infection and disease. ? ? ? ?
