Ronald Drew Etheridge

The Host-Parasite Interface; Identification and characterization of Toxoplasma gondii parasite effectors used to manipulate host cellular processes.

Our lab focuses primarily on the obligate intracellular pathogen Toxoplasma gondii.  This organism is arguably one of the most successful protozoan parasites on the planet with approximately a third of all human being infected. Although generally self-limiting, infections by T. gondii can be life threatening or fatal in individuals with immature or suppressed immune systems.  After resolution of the acute infection by the rapidly growing asexual form of T. gondii (tachyzoite), what remains is the chronic slow growing (bradyzoite) form of the parasite that encases itself in a highly resistant cyst wall.  These dormant tissue cysts persist throughout the lifetime of an individual and retain the capacity to reactivate if host conditions change. Currently there are no available drugs or therapeutics that can combat the chronic cyst form of the parasite and cure infection.

After active invasion of its target host cell, Toxoplasma resides within a host derived membrane ‘bubble’ known as the parasitophorous vacuole (PV) where it actively replicates over the next 48 hours.  To obtain the necessary nutrients and protect itself from antimicrobial defenses, this parasite has devised some extremely complex molecular tools that it deploys to manipulate the host environment to its advantage.  T. gondii injects into the host cell, via its secretory organelles, a myriad of protein effectors that traffic to various locations including the PV and host cell cytoplasm and nucleus. These secreted proteins accomplish a variety of goals ranging from organizing the nutrient acquisition machinery within the PV, protecting the vacuole from host defenses, and altering host cell metabolism and immune signaling pathways.  We currently do not know the exact number of effectors that the parasite employs during this process of host subjugation but, of those identified so far, only the functions of a few have been extensively characterized.  Additionally, almost nothing is known about the effectors that the bradyzoite form of the parasite uses to condition the host cell during the chronic stage of infection.

Overall our lab is seeking to address a variety of questions which relate broadly to the molecular tools used by the parasite to alter the host environment.  This work includes not only the continued study of known effectors, but also identification and characterization of new secreted proteins.  In a more comprehensive manner however we are also interested in how proteins destined for secretion are selected by the host sorting machinery and targeted to different secretory organelles.  Also, once secreted from the parasite into the PV it is currently unknown how particular proteins are then recognized and transported into the host cell.  In line with these goals, we are also working to identify parasite proteins that are selectively secreted by the cyst forming bradyzoite stage that are critical to the formation of not only the cyst wall but also in modifying the host cell to tolerate long term parasitism by Toxoplasma.