We study cellular signaling and the regulation of gene expression in a fascinating protozoan parasite called Toxoplasma gondii. Toxoplasma, a relative of the malarial parasite, causes congenital birth defects, as well as opportunistic infection in HIV/AIDS, cancer chemotherapy, and heart transplant patients. There is also emerging evidence that this parasitic infection may be linked to neurological disorders, such as schizophrenia and behavior modification. While the acute stage of toxoplasmosis can be treated, the ability of the parasite to convert into latent tissue cysts prevents eradication of the infection from the patient. Unfortunately, if immunity wanes, the patient can relapse and suffer additional episodes of life-threatening acute infection. Additionally, Toxoplasma is a serious threat to some wildlife and livestock.
We hypothesize that the proteins controlling parasite gene expression at epigenetic, transcriptional, and translational levels may represent novel drug targets to fight Toxoplasma and other infectious diseases.
More about what we do can be read in this news article.
EPIGENETICS & TRANSCRIPTION
We have been investigating epigenetic-based gene control in Toxoplasma since 2000. We cloned the first full-length histone lysine acetyltransferase (KAT) in Toxoplasma and subsequently demonstrated the importance of GCN5 family KATs in parasite viability and development.
Armed with the knowledge that GCN5 family KATs are crucial for Toxoplasma survival and development into latent cyst forms, we are further probing the interactomes of these enzymes, how they are mobilized, and how they connect with parasite-specific transcription factors.
Read more about our recent work at ScienceDaily.
THE ACETYLOME & CELLULAR SIGNALING
In addition to the GCN5 family KATs, we have characterized MYST and Elp3 KATs that localize beyond the parasite nucleus, suggesting non-nuclear proteins are also subject to acetylation in Toxoplasma. Elucidation of the parasite "acetylome" revealed hundreds of non-histone substrates in all compartments of the cell.
We are currently working to understand the biological consequences of lysine acetylation on various proteins and if this process can be targeted pharmacologically.
In collaboration with Dr. Ron Wek at IUSM, we discovered that the phosphorylation of Toxoplasma eukaryotic initiation factor-2 (eIF2), which governs the rate-limiting step of protein synthesis, is associated with microbial latency. Phosphorylation of eIF2 induces translational control that leads to reprogramming of the genome in response to stress or developmental cues.
We are working to characterize the eIF2 kinases in Toxoplasma and whether translational control can be manipulated to better treat infection.
Read this recent article about our work in this area.