William Sullivan, Ph.D.
Professor of Pharmacology & Toxicology
Professor of Microbiology and Immunology
Description and summary of research focus of the laboratory
We study the regulation of gene expression in a protozoan parasite called Toxoplasma gondii. Toxoplasma, a relative of the malaria parasite, causes congenital birth defects, as well as opportunistic infection in AIDS, cancer chemotherapy, and organ transplant patients. There is also recent evidence suggesting that this parasite is linked to neurological disorders, such as schizophrenia and behavior modification. We hypothesize that the proteins controlling gene expression at epigenetic, transcriptional, and translational levels may represent novel drug targets to fight Toxoplasma and other infectious diseases. We are particularly interested in the molecular mechanisms that govern how the parasite switches between its rapidly proliferating form and its latent cyst form.
Since the conversion to the cyst form is a stress-induced process, my laboratory has focused on investigating cellular stress pathways in this pathogen. We have discovered that eukaryotic initiation factor-2 (eIF2) phosphorylation plays a key role in cyst formation; eIF2 regulates protein translation in response to stress. We have also discovered numerous histone modifying enzymes that function to alter gene expression during stress-induced cyst formation, suggesting that epigenetic mechanisms also mediate cyst formation. Ongoing studies continue to examine the contributions of translational and transcriptional control in this clinically relevant protozoan. Not only does our research promise to illuminate new approaches to eliminate latent infections, but it also will provide valuable insight into the evolution of cellular signaling and gene regulation.
- Benmerzouga I, Checkley LA, Ferdig MT, Arrizabalaga G, Wek RC, Sullivan WJ Jr. (2015) Guanabenz repurposed as an anti-parasitic with activity against acute and latent toxoploamosis. Antimicrob Agents Chemother. Aug 24. pii: AAC.01683-15. [Epub ahead of print] PMID:26303803
- Herman JD, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Derbyshire ER, Ribacke U, Lukens AK, Santos SA, Patel V, Clish CB, Sullivan WJ Jr, Zhou H, Bopp SE, Schimmel P, Lindquist S, Clardy J, Mota MM, Keller TL, Whitman M, Wiest O, Wirth DF, Mazitschek R. (2015) The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci Transl Med. May 20;7(288):288ra77. doi: 10.1126/scitranslmed.aaa3575. PMID:25995223
- Bouchut A, Chawla AR, Jeffers V, Hudmon A, Sullivan WJ Jr. (2015) Proteome-wide lysine acetylation in cortical astrocytes and alterations that occur during infection with brain parasite Toxoplasma gondii. PLoS One. Mar 18;10(3):e0117966. doi: 10.1371/journal.pone.0117966. eCollection 2015. PMID: 25786129
- Wang J, Dixon SE, Ting L, Liu T, Jeffers V, Croken MM, Calloway M, Cannella D, Hakimi MA, Kim K, Sullivan Jr WJ (2014) Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation. PLoS Pathogens. 10(1):e1003830.
- Konrad C, Wek RC, Sullivan Jr WJ (2014) GCN2-like eIF2 kinase manages the amino acid starvation response in Toxoplasma gondii. International J Parasitology, 44:139-46. PMC3946947
- Nardelli SC, Che F-Y, Silmon de Monerri NC, Xiao H, Nieves E, Madrid-Aliste C, Angel SO, Sullivan Jr WJ, Angeletti RH, Kim K, Weiss LM (2013) The histone code of Toxoplasma gondii comprises conserved and unique post-translational modifications. mBio, 4(6):e00922-13.
- Stilger KL & Sullivan Jr WJ (2013) Elp3 lysine acetyltransferase is a tail-anchored mitochondrial protein in Toxoplasma gondii. J Biol Chem, 288:25318-29.
- Joyce BR, Tampaki Z, Kim K, Wek RC, Sullivan Jr WJ (2013) The unfolded protein response in protozoan parasite Toxoplasma gondii. Eukaryot Cell, 12:979-989.
- Radke JB, Lucas O, De Silva EK, Ma Y, Sullivan Jr WJ, Weiss LM, Llinas M, White MW (2013) ApiAP2 transcription factor restricts development of the Toxoplasma tissue cyst. PNAS, 110:6871-6.
- Konrad C, Queener SF, Wek RC, Sullivan Jr WJ (2013) Inhibitors of eIF2α dephosphorylation slow replication and stabilize latency in Toxoplasma gondii. Antimicrob Agents Chemother, 57:1815-22.
- B.S., 1992: Frostburg State University, Frostburg, MD
- Ph.D., 1997: University of Pennsylvania, Philadelphia, PA
- Postdoctoral, 1998-2000: ELANCO/Eli Lilly & Co., Greenfield, IN
- Assistant Scientist, 2000-2003: Indiana University School of Medicine, Indianapolis, IN