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William J. Sullivan, Jr., PhD

Professor of Pharmacology and Toxicology

Research Interest

We study cellular signaling and the regulation of gene expression in a protozoan parasite called Toxoplasma gondii, which inhabits the brain of nearly 25% of people in the US. Toxoplasma, a relative of the malarial parasite, causes congenital birth defects, as well as opportunistic infection in AIDS, cancer chemotherapy, and organ transplant patients. There is also evidence suggesting that this parasite is linked to behavior modification and to neurological disorders, such as schizophrenia, so in addition to studying the parasite’s biology in order to identify novel drug targets, we are engaged in work to understand how the parasite modifies brain cells.

Education

1992

B.S. Biology | Frostburg State University | Frostburg, Maryland

1994

M.S. Immunology | University of Pennsylvania | Philadelphia, Pennsylvania

1997

Ph.D. Molecular and Cell Biology | University of Pennsylvania | Philadelphia, Pennsylvania

Honors

2014-present Showalter Scholar
2014 Invited Speaker, Indianapolis Society for Neuroscience | Indianapolis, IN
2014 Invited Speaker, Midwest Neglected Infectious Disease Meeting | Notre Dame, IN
2014 Lecturer, Biology of Parasitism Course | Woods Hole, MA
2014 Pathology Grand Rounds Presentation | Indiana University School of Medicine
2013

Invited speaker, IFo-Tox (Interdisciplinary Forum on Toxoplasmosis) | Gottingen, Germany

2012

Trustee Teaching Award | Indiana University School of Medicine

2011

Invited speaker, the IX Argentine Congress of Protozoology and Parasitic Diseases | Argentina

2011

Invited speaker, Molecular Parasitology Meeting  Woods Hole,  MA

2011

Invited speaker, Midwest Neglected Infectious Disease Meeting | Notre Dame, IN

2011

Invited speaker, 11th International Congress on Toxoplasmosis | Ottawa, Canada

2010 Invited speaker | ASTMH
2010 Chair | Division AA | American Society for Microbiology
2009-present Editorial Board Member | Eukaryotic Cell
2009 Invited Speaker | 10th International Congress on Toxoplasmosis | Kerkrade, Netherlands
2008 Invited Speaker | Toxoplasma Centennial Congress | Buzios, Brazil
2008 Trustee Teaching Award | Indiana University School of Medicine 
2007

Invited Speaker | 9th International Congress on Toxoplasmosis | Chico Hot Springs, Montana

2007 Invited Speaker | ASM General 107th Meeting | Toronto, Canada
2005-2006

Showalter Trust Fund Award | Indiana University School of Medicine

2005

Invited Speaker | Molecular Parasitology Meeting | Woods Hole, Massachusetts

2004

Invited Speaker | Molecular Parasitology Meeting | Woods Hole, Massachusetts

2003-2004

Invited Speaker | 7th International Congress on Toxoplasmosis | New York, New York

 

Go to Sullivan Lab Site

My laboratory is interested in how cells regulate gene expression at multiple levels, including transcription, epigenetics, translational control, and post-translational modification. We study these mechanisms in a protozoan parasite called Toxoplasma gondii, which is a notorious opportunistic infection endangering AIDS and other immunocompromised patients. In addition to its clinical importance, Toxoplasma also serves as a useful model for the study of less tractable parasites such as malaria.

Toxoplasma is a fascinating parasite that is capable of infecting any nucleated cell in warm-blooded vertebrates. Consequently, it is found throughout the world and has emerged as a significant food and waterborne pathogen. One of the most remarkable features of its biology is the ability to convert into a latent tissue cyst, mostly in the brain and heart of the host. If immunity wanes, the parasite begins to replicate again, causing life-threatening acute disease. There are reports that even in otherwise healthy people, the presence of these parasite brain cysts can lead to a wide spectrum of neurological disorders.

My laboratory is elucidating how the parasite can switch between replicative and dormant forms. We have discovered that conditions causing cyst formation induce an “integrated stress response” that mediates translational control through phosphorylation of eukaryotic initiation factor-2 (eIF2). In other words, general protein production is reduced and specialized mRNAs are preferentially translated under these conditions. These mRNAs encode for proteins that allow for adaptation and include a set of parasite-specific transcription factors that are not present in humans. Additionally, epigenetic machinery is recruited by these transcription factors to fully activate gene expression. We also discovered that some of the epigenetic machinery, namely lysine acetyltransferases (KATs), targets hundreds more substrates beyond histones. So in addition to investigating how gene expression is controlled, we are also studying the functions of these widespread protein modifications. Genetic and pharmacologic interference with these systems subvert parasite replication and/or stage conversion and may lead to innovative new ways to treat infection.

  • Herman J, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Deryshire ER, Ribacke U, Lukens AK, Santos SA, Patel V, Clish CB, Sullivan Jr WJ, 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 Tranl Med. 7(288): p.288ra77.
  • Bouchut A, Chawla AR, Jeffers V, Hudmon A, Sullivan WJ Jr. Proteome-Wide Lysine Acetylation in Cortical Astrocytes and Alterations That Occur during Infection with Brain Parasite Toxoplasma gondii. PLoS ONE. 2015 Mar 18;10(3):e0117966. doi: 10.1371/journal.pone.0117966. eCollection 2015. PMID: 25786129  PRESS RELEASE. Featured on IFLScience.
  • Arrizabalaga G and Sullivan WJ Jr. Common Parasite Could Manipulate Our Behavior. Scientific American MIND. 2015 Mar; 26(2). This article was also featured on Salon.com.
  • Bogado SS, Dalmasso C, Ganuza A, Kim K, Sullivan WJ Jr, Angel SO, Vanagas L. Canonical histone H2Ba and H2A.X dimerize in an opposite genomic localization to H2A.Z/H2B/Z dimers in Toxoplasma gondii. Mol Biochem Parasitol. 2014 Oct 5. pii: S0166-6851(14)00139-X. doi: 10.1016/j.molbiopara.2014.09.009. [Epub ahead of print] PMID: 25286383
  • Liu M, Miao J, Liu T, Sullivan WJ Jr, Cui L, Chen X. Characterization of TgPuf1, a member of the Puf family RNA-binding proteins fromToxoplasma gondii. Parasit Vectors. 2014 Mar 31;7(1):141. PMID: 24685055
  • Wang J, Dixon SE, Ting LM, Liu TK, Jeffers V, Croken MM, Calloway M, Cannella D, Ali Hakimi M, Kim K, Sullivan WJ Jr. Lysine Acetyltransferase GCN5b Interacts with AP2 Factors and Is Required for Toxoplasma gondii Proliferation. PLoS Pathog. 2014 Jan;10(1):e1003830. doi: 10.1371/journal.ppat.1003830. Epub 2014 Jan 2. PMID: 24391497  PRESS RELEASE
  • Konrad C, Wek RC, Sullivan WJ Jr. GCN2-like eIF2a kinase manages the amino acid starvation response in Toxoplasma gondii. Int J Parasitol. 2014 Feb;44(2):139-46. PMID: 24126185
  • Nardelli SC, Che FY, Silmon de Monerri NC, Xiao H, Nieves E, Madrid-Aliste C, Angel SO, Sullivan WJ Jr, Angeletti RH, Kim K, Weiss LM. The Histone Code of Toxoplasma gondii Comprises Conserved and Unique Posttranslational Modifications. MBio. 2013 Dec 10;4(6). PMID: 24327343
  • Stilger KL and Sullivan WJ Jr. Elp3 lysine acetyltransferase is a tail-anchored mitochondrial protein in Toxoplasma gondii. J Biol Chem. 2013. 288(35):25318-29. PMID: 23878194 Featured in ASBMB Today
  • Miao J, Lawrence M, Jeffers V, Zhao F, Parker D, Ge Y, Sullivan WJ Jr, Cui L. Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. Mol Microbiol. 2013 Jun 24. doi: 10.1111/mmi.12303. [Epub ahead of print]. PMID: 23796209
  • Joyce BR, Tampaki Z, Kim K, Wek RC, Sullivan WJ Jr. The Unfolded Protein Response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control. Eukaryot Cell. 2013 Jul;12(7):979-89. PMID: 23666622
  • Radke JB, Lucas O, De Silva EK, Ma Y, Sullivan WJ Jr, Weiss LM, Llinas M, White MW. ApiAP2 transcription factor restricts development of the Toxoplasma tissue cyst. Proc Natl Acad Sci U S A. 2013 2013 Apr 23;110(17):6871-6. PMID: 23572590 PRESS RELEASE
  • Konrad C, Queener SF, Wek RC, Sullivan WJ Jr. Inhibitors of eIF2a Dephosphorylation Slow Replication and Stabilize Latency in Toxoplasma gondii. Antimicrob Agents Chemother. 2013 Apr;57(4):1815-1822. PMID: 23380722  PRESS RELEASE
  • Xue B*, Jeffers V*, Sullivan WJ+, Uversky VN+. Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii. Mol Biosyst. 2013 Apr 5;9(4):645-57. doi: 10.1039/c3mb25517d. PMID: 23403842. * joint first-author, + joint corresponding author.
  • Lindner SE, Mikolajczak SA, Vaughan AM, Moon W, Joyce BR, Sullivan WJ Jr, Kappe SH. Perturbations of Plasmodium Puf2 Expression and RNA-seq of Puf2-Deficient Sporozoites Reveal a Critical Role in Maintaining RNA Homeostasis and Parasite Transmissibility. Cell Microbiol. 2013 Jan 29. doi: 10.1111/cmi.12116. [Epub ahead of print] PMid: 23356439
  • Zhang M, Joyce BR, Sullivan WJ Jr, Nussenzweig V. Translational control in Plasmodium and Toxoplasma parasites. Eukaryot Cell. 2013 Feb;12(2):161-7. PMID: 23243065  Featured at "Mapping Ignorance"
  • Vanagas L, Jeffers V, Bogado SS, Dalmasso MC, Sullivan WJ Jr, Angel SO. Toxoplasma histone acetylation remodelers as novel drug targets. Expert Rev Anti Infect Ther. 2012 Oct;10(10):1189-201. PMID: 23199404
  • Jeffers V and Sullivan WJ Jr. Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii. Eukaryotic Cell. 2012 Jun;11(6):735-42. PMID: 22544907
  • Zhang M, Mishra S, Sakthivel R, Rojas M, Ranjan R, Sullivan WJ Jr, Fontoura BM, Ménard R, Dever TE, Nussenzweig V. PK4, a eukaryotic initiation factor 2a(eIF2a) kinase, is essential for the development of the erythrocytic cycle of Plasmodium. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3956-61. Epub 2012 Feb 21. PMID: 22355110 
  • Figueras MJ, Martin OA, Echeverria PC, de Miguel N, Naguleswaran A, Sullivan WJ Jr, Corvi MM, Angel SO. Toxoplasma gondii Sis1-like J-domain protein is a cytosolic chaperone associated to HSP90/HSP70 complex. Int J Biol Macromol. 2012 Apr 1;50(3):725-33. Epub 2011 Dec 23. PMID: 22209934
  • Sullivan WJ Jr, Jeffers V. Mechanisms of Toxoplasma gondii persistence and latency. FEMS Microbiol Rev. 2012 May;36(3):717-33. PMID: 22091606
  • Konrad C, Wek RC, Sullivan WJ Jr. A GCN2-like eukaryotic initiation factor 2 kinase increases the viability of extracellular Toxoplasma gondii parasites. Eukaryot Cell. 2011 Nov;10(11):1403-12. Epub 2011 Sep 9. PMID: 21908594
  • Dalmasso MC, Sullivan WJ, Angel SO. Canonical and variant histones of protozoan parasites. Front Biosci. 2011 Jun 1;17:2086-2105. PMID: 21622164
  • Onyango DO, Naguleswaran A, Delaplane S, Reed A, Kelley MR, Georgiadis MM, Sullivan WJ Jr. Base excision repair apurinic/apyrimidinic endonucleases in apicomplexan parasite Toxoplasma gondii. DNA Repair (Amst). 2011 May 5;10(5):466-75. Epub 2011 Feb 24. PMID:21353648
  • Joyce BR, Konrad C, Wek RC, Sullivan WJ Jr. Translation control is critical during acute and chronic stages of toxoplasmosis infection. Expert Rev Anti Infect Ther. 2011 Jan;9(1):1-3. PMID: 21171869
  • Dixon SE, Bhatti MM, Uversky VN, Dunker AK, Sullivan WJ Jr. Regions of intrinsic disorder help identify a novel nuclear localization signal in Toxoplasma gondii histone acetyltransferase TgGCN5-B. Mol Biochem Parasitol. 2011 Feb;175(2):192-5 PMID: 21055425
  • Naguleswaran A, Elias EV, McClintick J, Edenberg HJ, Sullivan WJ. Toxoplasma gondii Lysine Acetyltransferase GCN5-A Functions in the Cellular Response to Alkaline Stress and Expression of Cyst Genes. PLoS Pathog. 2010 Dec 16;6(12):e1001232. PMID: 21179246 
  • Joyce BR, Queener SF, Wek RC, Sullivan WJ Jr. Phosphorylation of eukaryotic initiation factor-2{alpha} promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondii. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17200-5 PMID: 20855600  PRESS RELEASE
  • Zhang M, Fennell C, Ranford-Cartwright L, Sakthivel R, Gueirard P, Meister S, Caspi A, Doerig C, Nussenzweig RS, Tuteja R, Sullivan WJ Jr, Roos DS, Fontoura BM, Ménard R, Winzeler EA, Nussenzweig V. The Plasmodium eukaryotic initiation factor-2{alpha} kinase IK2 controls the latency of sporozoites in the mosquito salivary glands. J Exp Med. 2010 Jul 5;207(7):1465-74. PMID: 20584882
  • Dixon SE, Stilger KL, Elias EV, Naguleswaran A, Sullivan WJ Jr. A decade of epigenetic research in Toxoplasma gondii. Mol Biochem Parasitol. 2010 Sep;173(1):1-9. Epub 2010 May 12. PMID: 20470832

Department of Pharmacology and Toxicology | 635 Barnhill Drive, MS A401 | Indianapolis, IN 46202