Susan C. Baker, Ph.D

Susan C. Baker, Ph.D

Professor

Ph.D., Vanderbilt University

Major Research Interests: The molecular biology and pathogenesis of coronaviruses. The etiology and pathogenesis of Kawasaki Disease

Coronaviruses 

The focus of my research is to study how viruses replicate and cause disease. One major area of our research is to investigate the replication of coronaviruses, including the coronavirus that caused the outbreak of Severe Acute Respiratory Syndrome (SARS). We study the expression, proteolytic processing and function of the coronavirus RNA polymerase polyprotein. This complex polyprotein holds the key to understanding how coronavirus replication is regulated. We found that the polyprotein is processed into 16 products by viral proteases. Viral proteases are attractive targets for antiviral drug development. Our research efforts are evaluating protease inhibitors as antiviral drugs and determining if viral proteases block the innate immune response to facilitate viral replication. 

Kawasaki Disease

We also study the etiology and pathogenesis of Kawasaki Disease (KD). KD is the leading cause of acquired heart disease in children in developed nations, but the cause of KD is unknown. Using KD-specific antibodies, my collaborator Dr. Anne Rowley showed that an antigen is found in both the coronary arteries and in bronchial epithelial cells of KD patients, suggesting a respiratory portal of entry for the KD agent. We are using human airway epithelial cell cultures to identify and propagate microbes associated with KD.  We also exploit PCR arrays to profile gene expression in KD lung and coronary artery tissue to investigate mechanisms of pathogenesis. 

Deng, X.,  A. Mielech, M. Hackbart, R. Mettelman, A. O’Brien, G. Yi, C. C. Kao and Susan C. Baker. (2017). Coronavirus Nonstructural Protein 15 Mediates Evasion of dsRNA Sensors and Limits Apoptosis in Macrophages.  Proc. Natl. Acad. Sci. (in press).

Rowley, A.H., Baker, S.C., Kim, K.A., Shulman, S.T., Yang, A., Arrollo, D., DeBerge, M., Han, S., Sibinga, N.E.S., Pink, A.J., and E.B. Thorp. (2017). Allograft Inflammatory Factor-1 links T cell activation, interferon response, and macrophage activation in chronic Kawasaki Disease arteritis. Journal of the Pediatric Infectious Disease Society (in press). 

Clasman, J.R., Baez-Santos, Y.M., Mettelman, R.C., O’Brien, A., Baker, Susan C. and A.D. Mesecar. (2017). X-ray structure and enzymatic activity profile of a core papain-like protease of MERS Coronavirus with utility for Structure-based Drug Design. Nature Scientific Reports 7, 40292; doi: 10.1038/srep40292.

Rowley, Anne H., Wylie, Kristine M., Kim, Kwang-Youn A., Pink, Adam J., Yang, Amy, Reindel, Rebecca, Baker, Susan C., Shulman, Stanford T., Orenstein, Jan M., Lingen, Mark W., Weinstock, George M., Wylie, Todd N. (2015). The transcriptional profile of coronary arteritis in Kawasaki Disease.  BMC Genomics 2015; 16:1076. PMCID: PMC4683744.

Chen, Yafang S. N. Savinov, A.M. Mielech, T. Cao, P.C. Montenegro, Susan C. Baker and A.D. Mesecar.  (2015). X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions. Journal of Biological Chem 290: 25293-25306.

Miller, Nicholas, R.C. Mettelman, Susan C. Baker and Justin E. Harbison. (2015). Use of CDC gravid traps in catch basins:  proof-of-concept trials.  Journal of the American Mosquito Control Association 31(2): 196-199.

Mielech, Anna M., X. Deng, Y. Chen, E.  Kindler, D.L. Wheeler, A.D. Mesecar, V. Thiel, S. Perlman and Susan C. Baker.  (2015). Murine coronavirus ubiquitin-like domain 2 is important for papain-like protease stability and viral pathogenesis. J. Virol. 89: 4907-4917. Selected by the editors for the “Spotlight.”

Deng, Xufang, Sarah E. St. John, Heather L. Osswald, Amornrat O’Brien, Bridget S. Banach, Katrina Sleeman, Arun K. Ghosh, Andrew D. Mesecar, and Susan C. Baker. (2014). Coronaviruses Resistant to a 3C-like Protease Inhibitor Are Attenuated for Replication and Pathogenesis Revealing a Low Genetic Barrier but High Fitness Cost of Resistance.  J. Virol. 88: 11886-11898.

Deng, Xufang, Sudhakar Agnihothram,Anna M. Mielech, Daniel. B. Nichols, Michael. W. Wilson, Sarah St. John, Scott. D. Larsen, Andrew. D. Mesecar, Deborah. J. Lenschow, Ralph S. Baric and Susan. C. Baker.  (2014). A Chimeric Virus-Mouse Model System for Evaluating the Function and Inhibition of Papain-like Proteases of Emerging Coronaviruses. J. Virol 88: 11825-11833.

Baez-Santos, Y.M., A.M. Mielech, X. Deng, Susan C. Baker and A.D. Mesecar. (2014). Catalytic function and substrate specificity of the PLpro domain of nsp3 from the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). J. Virol. 88: 12511-12527.

Reindel, Rebecca, Jared Bischof, Kwang-Youn A. Kim, Jan Orenstein, Marcelo B. Soares, Susan C. Baker, Stanford T. Shulman, Elizabeth J. Perlman, Mark W. Lingen, Cynthia Trevenen, Anne H. Rowley. (2014). CD84 is markedly Upregulated in Kawasaki Disease Arteriopathy.  Clinical & Experimental Immunology 177: 203-211.

Al-Mulla, H.M.N., L. Turrell, N.M. Smith, L. Payne, S. Baliji, R. Zust, V. Thiel, Susan C. Baker, S.G. Siddell and B.W. Neuman.  (2014). Competitive fitness in coronaviruses is not correlated with size or number of double-membrane vesicles under reduced temperature growth conditions.  mBio 5(2):e01107-13. doi: 10.1128/mBio.01107-13. 

Ratia K, Kilianski A, Baez-Santos YM, Baker SC, Mesecar A (2014) Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS CoV Papain-Like Protease. PLoS Pathog 10(5): e1004113. doi:10.1371/journal.ppat.1004113

Reindel, Rebecca, Kwang-Youn A. Kim, Jan Orenstein, Susan C. Baker, Stanford T. Shulman, Elizabeth J. Perlman, Mark W. Lingen, Cynthia Trevenen, Anne H. Rowley. 2014. Periostin is upregulated in coronary arteriopathy in Kawasaki Disease and is a potential diagnostic biomarker. Pediatric Infectious Disease Journal 33: 659-661.

Mielech, Anna M, Andy Kilianski, Yahira M. Baez-Santos, Andrew D. Mesecar and Susan C. Baker. 2014.  MERS-CoV Papain-like Protease has deISGylating and deubiquitinating activities. Virology 450: 64-70.

Baez-Santos, Yahira M., Barraza, Scott J.; Wilson, Michael W.; Agius, Michael P.; Mielech, Anna; Davis, Nicole M.; Baker, Susan C.; Larsen, Scott; and Andrew D. Mesecar. 2014. X-Ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain Like-Proteases. J. Med Chem 56: 534-546.

Kilianski, Andy, Anna Mielech, Xufang Deng and Susan C. Baker. 2013. Assessing Activity and Inhibition of MERS-CoV Papain-like and 3C-like Proteases Using Luciferase-based Biosensors. J. Virol. 87: 11955-11962. (Selected for “Spotlight” by the Editors).

de Groot, Raoul, J., Susan C. Baker, Ralph S. Baric, Caroline S. Brown, Christian Drosten, Luis Enjuanes, Ron A.M. Fouchier, Monica Galiano, Alexander E. Gorbalenya, Ziad Memish, Stanley Perlman, Leo L.M. Poon, Eric J. Snijder, Gwen M. Stephens4 Patrick C.Y. Woo, Ali M. Zaki, Maria Zambon, John Ziebuhr (2013).  Middle East Respiratory Syndrome Coronavirus (MERS-CoV):  Announcement of the Coronavirus Study Group. J. Virol. 87, 7790-7792.

Xing, Yaling, Jianfei Chen, Jian Tu, Bailing Zhang, Xiaojuan Chen, Hongyan Shi, Susan C. Baker, Li Feng, and Zhongbin Chen.  2013.  The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase.  Journal of General Virology 94, 1554-1567.

Jacobs, Jon, Valerie Grum-Tokars, Ya Zhou, Mark Turlington, S. Adrian Saldanha, Peter Chase, Aimee Eggler, Eric S. Dawson, Yahira M. Baez-Santos, Sakshi Tomar, Anna M. Mielech, Susan C. Baker, Craig W. Lindsley, Peter Hodder, Andrew Mesecar, and Shaun R. Stauffer. 2013.  Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease.  Journal of Medicinal Chemistry 56 (2), 534-546. PMCID: PMC3569073

Beachboard, D.C., X. Lu, S.C. Baker, and M.R. Denison. 2013. Murine hepatitis virus nsp4 N258T mutants are not temperature-sensitive. Virology 435: 210-213.

Reindel, R., Susan C. Baker, Kwang-Youn Kim, Carol Rowley, Stanford Shulman, Jan Orenstein, Elizabeth Perlman, Mark Lingen, and Anne Rowley.  2013.  Integrins Alpha4 and Alpha M, Collagen1A1, and Matrix Metalloproteinase 7 Are Upregulated in Acute Kawasaki Disease Vasculopathy.  Pediatric Research doi: 10.1038/pr2012.185.

Orenstein, J. M., S. T. Shulman, L. M. Fox, S. C. Baker, T. R. Bhatti, P. A. Russo, J.  P. De Chadarevian, E. J. Perlman, C. Trevenen, M. Takahashi, G. Mierau, M. B. Kalelkar, A. Rotta, and A. H. Rowley.  2012. Three Vasculopathic Processes Characterize Kawasaki Disease:  A Light and Transmission Electron Microscopic Study.  PLoS One 7:e38998.

Elshabrawy, H.A., Melissa M. Coughlin, Susan C. Baker, Bellur S. Prabhakar. 2012.  Human Monoclonal Antibodies against Highly Conserved HR1 and HR2 Domains of the SARS-CoV Spike Protein Are More Broadly Neutralizing. Research Article | published 21 Nov 2012 | PLOS ONE 10.1371/journal.pone.0050366

Sun, L., Y. Yang, X. Chen, Y. Xing, D. B. Nichols, M. A. Clementz, B. S. Banach, K. Li, S. C. Baker, Z. Chen. 2012. Coronavirus papain-like proteases negatively regulate the innate immune response through disruption of STING-mediated signaling. PLoS ONE 7(2): e30802.

Zust, R., L. Cervantes-Barragan, M. Habjan, R. Maier, B. W. Neuman, J. Ziebuhr, S. C. Baker, W. Barchet, S. G. Siddell, B. Ludewig, V. Thiel. 2011. Ribose 2′-O-methylation provides a molecular signature for MDA5-mediated distinction of self and non-self mRNA.  Nature Immunology, 12, 137-147.

Stokes, H.L., S. Baliji, C.G. Hui, S.G. Sawicki, S.C. Baker and S.G. Siddell.  (2010).  A New Cistron in the Murine Hepatitis Virus Replicase Gene.  J. Virol. Epub online 28 July 2010.

Rowley, A. H., S. C. Baker, S. T. Shulman, K. H. Rand, M. S. Tretiakova, E. J. Perlman, F. L. Garcia, N. F. Tajuddin, L. M. Fox, J. H. Huang, J. C. Ralphe, K. Takahashi, J. Flatow, S. Lin, M. B. Kalelkar, B. Soriano, J. M. Orenstein. 2011. Ultrastructural, immunofluorescence, and RNA evidence support the hypothesis of a "new" virus associated with Kawasaki Disease. Journal of Infectious Diseases 203, 1021-1030.

Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S,Baker SC, Johnson ME, Mesecar AD. Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.  J Med Chem. 2010 Jul 8;53(13):4968-79.

Clementz MA, Chen Z, Banach BS, Wang Y, Sun L, Ratia K, Baez-Santos YM, Wang J, Takayama J, Ghosh AK, Li K, Mesecar AD, Baker SC. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. J Virol. 2010 May;84(9):4619-29. Epub 2010 Feb 24.

 

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