Sustenance

The team is exposing the functions of parasite proteases including most notably a digestive enzyme termed cathepsin protease L. We showed that cathepsin protease L is the first marker of a novel and dynamic parasite digestive organelle termed the vacuolar compartment or VAC (also known as the PLV)(1). We are using selective protease inhibitors and genetic mutants to determine the protease substrate range (2,3), specific role in invasion and replication and to test the efficacy of inhibitory compounds for ameliorating latent infection . Of note, these studies are revealing for the first time that the parasite internalizes and digests material from the host cell cytoplasm during intracellular replication, indicating that T. gondii is a heterophage ("other eat") (4). We are investigating the extent to which the parasite uses this uptake pathway to satisfy its nutritional demands, thwart host immune effectors and support the long-term survival of the parasite in neural cysts.

1. Parussini, F., Coppens, I., Shah, P., Diamond, S.L., and Carruthers, V.B. (2010) Cathepsin L occupies a vacuolar compartment and is a protein maturase within the endo/exosomal system of Toxoplasma gondii. 76;1340-1357. Mol. Microbiol.

2. Larson, E.T., Parussini, F., Huynh, M.-H., Giebel, J.D., Kelley, A.M., Zhang, L., Bogyo, M., Merritt, E.A., and Carruthers, V.B. (2009) Toxoplasma gondii Cathepsin L as the primary target of the invasion inhibitory compound LHVS. J. Biol. Chem. 284;26839-26850.

3. Dou, Z., Coppens, I., and Carruthers, V.B. (2013) Non-canonical maturation of two papain-family proteases in Toxoplasma gondii J. Biol. Chem. 288:3523-3534.

4. Dou, Z., McGovern, O.L., Di Cristina, M., Carruthers, V.B. (2014) Toxoplasma gondii ingests and digests host cytosolic proteins. mBio. e01188-14.