Microbiology and Immunology
Education and Training
- Washington University in St Louis, BA, Biology, 1994-1998
- Johns Hopkins University School of Medicine, Baltimore MD, Cellular and Molecular Medicine Graduate Program, Department of Molecular Biology and Genetics, PhD, 1998-2004
- University of North Carolina at Chapel Hill, Post-doctoral fellow in the lab of Dr. Ralph Baric, Department of Epidemiology/Department of Microbiology and Immunology, 2004-2009
My overall research goal is to create therapeutic interventions for viruses of public health concern by developing a detailed understanding of how the viruses interact with the host. My research has focused on the recently emerged and highly pathogenic coronaviruses: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Both viruses cause severe lung disease, are highly lethal and yet there are no FDA approved therapeutics that target them.
Important to understanding these diseases has been our development, characterization and utilization of mouse models of disease for both SARS-CoV and MERS-CoV. The rapid and successful development of these models has allowed us to unravel the cellular and physiological basis for disease of these viruses. In addition, the creation of these models has allowed for therapeutic development of vaccines, antibodies, small molecules, novel and repurposed drugs and other therapeutics. Critical to my research is the synergy of our in vitro and in vivo models of disease that allow us deep understandings of how these viruses work.
New recent work also focuses on Influenza virus, Norovirus and Rotavirus via in vitro yeast experiments described below. This new model uses yeast genetics platforms I used during my graduate school training synergizing with my current interest in viruses. Together we use yeast screens for functional genetic screens and high throughput drug screens to identify anti-viral interaction networks. We then model these networks in mammalian cells to identify proteins and pathways that effect virus replication as well as drugs that inhibit these same pathways, that are then tested using in vivo models of these pathogens. Combining our in vitro and in vivo systems identifies key proteins and nodes of regulation for further therapeutic targeting.
Coronavirus, MERS, SARS, Influenza, Norovirus, Pathogenesis, anti-viral, therapeutics, diabetes, DPP4, lung
Coleman CM, Venkataraman T, Liu YV, Glenn GM, Smith GE, Flyer DC, Frieman MB. 2017. MERS-CoV spike nanoparticles protect mice from MERS-CoV infection. Vaccine 35:1586-1589.
Coleman CM, Sisk JM, Halasz G, Zhong J, Beck SE, Matthews KL, Venkataraman T, Rajagopalan S, Kyratsous CA, Frieman MB. CD8+ T cells and Macrophages Regulate Pathogenesis in a Mouse Model of MERS-CoV Disease. J Virol. 2016 Oct26. pii:JVI.01825-16.
Coleman CM, Sisk JM, Mingo RM, Nelson EA, White JM, Frieman MB. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J Virol. 2016 Sep 12;90(19):8924-33. doi: 10.1128/JVI.01429-16.
Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, Hunt C, Strein J, Berrebi A, Sisk JM, Matthews KL, Babb R, Chen G, Lai KM, Huang TT, Olson W, Yancopoulos GD, Stahl N, Frieman MB, Kyratsous CA. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8738-43.
Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Matsushita H, Liu Y, Postnikova EN, Ork BL, Glenn G, Flyer D, Defang G, Raviprakash K, Kochel T, Wang J, Nie W, Smith G, Hensley LE, Olinger GG, Kuhn JH, Holbrook MR, Johnson RF,Perlman S, Sullivan E, Frieman MB. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med. 2016 Feb17;8(326):326ra21. doi: 10.1126/scitranslmed.aaf1061. PubMed PMID: 26888429.
Taylor JK, Coleman CM, Postel S, Sisk JM, Bernbaum JG, Venkataraman T, Sundberg EJ, Frieman MB. Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference. J Virol. 2015 Dec;89(23):11820-33. doi:10.1128/JVI.02274-15. PubMed PMID: 26378163; PubMed Central PMCID: PMC4645327.
Dyall, J., C. M. Coleman, B. J. Hart, T. Venkataraman, M. R. Holbrook, J. Kindrachuk, R. F. Johnson, G. G. Olinger, Jr., P. B. Jahrling, M. Laidlaw, Hensley L, and Frieman M. 2014. Repurposing of clinically developed drugs for treatment of middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 58:4885-93. PubMed PMID: 24841273.
1. Frieman MB, Chen ZJ, Saez-Vasquez J, Shen LA, Pikaard CS. 1999. RNA polymerase I transcription in a Brassica interspecific hybrid and its progenitors: Tests of transcription factor involvement in nucleolar dominance. Genetics 152:451-460.
2. Frieman MB, McCaffery JM, Cormack BP. 2002. Modular domain structure in the Candida glabrata adhesin Epa1p, a beta1,6 glucan-cross-linked cell wall protein. Mol Microbiol 46:479-492.
3. Strichman-Almashanu LZ, Lee RS, Onyango PO, Perlman E, Flam F, Frieman MB, Feinberg AP. 2002. A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome Res 12:543-554.
4. Frieman MB, Cormack BP. 2003. The omega-site sequence of glycosylphosphatidylinositol-anchored proteins in Saccharomyces cerevisiae can determine distribution between the membrane and the cell wall. Mol Microbiol 50:883-896.
5. Frieman MB, Cormack BP. 2004. Multiple sequence signals determine the distribution of glycosylphosphatidylinositol proteins between the plasma membrane and cell wall in Saccharomyces cerevisiae. Microbiology 150:3105-3114.
6. Yount B, Roberts RS, Sims AC, Deming D,Frieman MB, Sparks J, Denison MR, Davis N, Baric RS. 2005. Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice. J Virol 79:14909-14922.
7. Baric RS, Sheahan T, Deming D, Donaldson E, Yount B, Sims AC, Roberts RS, Frieman MB, Rockx B. 2006. SARS coronavirus vaccine development. Adv Exp Med Biol 581:553-560.
8. Frieman MB, Yount B, Sims AC, Deming DJ, Morrison TE, Sparks J, Denison M, Heise M, Baric RS. 2006. SARS coronavirus accessory ORFs encode luxury functions. Adv Exp Med Biol 581:149-152.
9. Frieman MB, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS. 2007. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol 81:9812-9824.
10. Kopecky-Bromberg SA, Martinez-Sobrido L, Frieman MB, Baric RA, Palese P. 2007. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol 81:548-557.
11. Wathelet MG, Orr M, Frieman MB, Baric RS. 2007. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol 81:11620-11633.
12. Frieman MB, Baric R. 2008. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev 72:672-685, Table of Contents.
13. Frieman MB, Heise M, Baric R. 2008. SARS coronavirus and innate immunity. Virus Res 133:101-112.
14. Zupancic ML, Frieman MB, Smith D, Alvarez RA, Cummings RD, Cormack BP. 2008. Glycan microarray analysis of Candida glabrata adhesin ligand specificity. Mol Microbiol 68:547-559.
15. Rockx B, Baas T, Zornetzer GA, Haagmans B, Sheahan T, Frieman MB, Dyer MD, Teal TH, Proll S, van den Brand J, Baric R, Katze MG. 2009. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 83:7062-7074.
16. Frieman MB, Ratia K, Johnston RE, Mesecar AD, Baric RS. 2009. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol 83:6689-6705.
17. Day CW, Baric R, Cai SX, Frieman MB, Kumaki Y, Morrey JD, Smee DF, Barnard DL. 2009. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology 395:210-222.
18. Basu D, Walkiewicz MP, Frieman MB, Baric RS, Auble DT, Engel DA. 2009. Novel influenza virus NS1 antagonists block replication and restore innate immune function. J Virol 83:1881-1891.
19. Donaldson EF, Haskew AN, Gates JE, Huynh J, Moore CJ, Frieman MB. 2010. Metagenomic analysis of the viromes of three North American bat species: viral diversity among different bat species that share a common habitat. J Virol 84:13004-13018.
20. Freundt EC, Yu L, Goldsmith CS, Welsh S, Cheng A, Yount B, Liu W, Frieman MB, Buchholz UJ, Screaton GR, Lippincott-Schwartz J, Zaki SR, Xu XN, Baric RS, Subbarao K, Lenardo MJ. 2010. The open reading frame 3a protein of severe acute respiratory syndrome-associated coronavirus promotes membrane rearrangement and cell death. J Virol 84:1097-1109.
21. Frieman MB, Chen J, Morrison TE, Whitmore A, Funkhouser W, Ward JM, Lamirande EW, Roberts A, Heise M, Subbarao K, Baric RS. 2010. SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6:e1000849.
22. Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, Bradel-Tretheway BG, Korth MJ, Castle JC, Biery MC, Bouzek HK, Haynor DR, Frieman MB,Heise M, Raymond CK, Baric RS, Katze MG. 2010. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. MBio 1.
23. Rockx B, Donaldson E, Frieman MB, Sheahan T, Corti D, Lanzavecchia A, Baric RS. 2010. Escape from human monoclonal antibody neutralization affects in vitro and in vivo fitness of severe acute respiratory syndrome coronavirus. J Infect Dis 201:946-955.
24. Zornetzer GA, Frieman MB, Rosenzweig E, Korth MJ, Page C, Baric RS, Katze MG. 2010. Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection. J Virol 84:11297-11309.
25. Peng X, Gralinski L, Ferris MT, Frieman MB, Thomas MJ, Proll S, Korth MJ, Tisoncik JR, Heise M, Luo S, Schroth GP, Tumpey TM, Li C, Kawaoka Y, Baric RS, Katze MG. 2011. Integrative deep sequencing of the mouse lung transcriptome reveals differential expression of diverse classes of small RNAs in response to respiratory virus infection. MBio 2.
26. Frieman MB, Basu D, Matthews K, Taylor J, Jones G, Pickles R, Baric R, Engel DA. 2011. Yeast based small molecule screen for inhibitors of SARS-CoV. PLoS One 6:e28479.
27. Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kelada SN, Collins FS, Yang IV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Liu EY, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, de Villena FP, Churchill GA. 2011. Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res 21:1213-1222.
28. Chen WH, Toapanta FR, Shirey KA, Zhang L, Giannelou A, Page C, Frieman MB, Vogel SN, Cross AS. 2012. Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza. Immunol Lett 141:227-234.
29. Frieman MB, Yount B, Agnihothram S, Page C, Donaldson E, Roberts A, Vogel L, Woodruff B, Scorpio D, Subbarao K, Baric RS. 2012. Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease. J Virol 86:884-897.
30. Huynh J, Li S, Yount B, Smith A, Sturges L, Olsen JC, Nagel J, Johnson JB, Agnihothram S, Gates JE, Frieman MB, Baric RS, Donaldson EF. 2012. Evidence supporting a zoonotic origin of human coronavirus strain NL63. J Virol 86:12816-12825.
31. Page C, Goicochea L, Matthews K, Zhang Y, Klover P, Holtzman MJ, Hennighausen L, Frieman MB. 2012. Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection. J Virol 86:13334-13349.
32. Coleman CM, Frieman MB. 2013. Emergence of the Middle East respiratory syndrome coronavirus. PLoS Pathog 9:e1003595.
33. Adedeji AO, Singh K, Kassim A, Coleman CM, Elliott R, Weiss SR, Frieman MB, Sarafianos SG. 2014. Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses. Antimicrob Agents Chemother 58:4894-4898.
34. Coleman CM, Frieman MB. 2014. Treating MERS-CoV during an outbreak. Lancet Infect Dis 14:1030-1031.
35. Matthews KL, Coleman CM, van der Meer Y, Snijder EJ, Frieman MB. 2014. The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling. J Gen Virol 95:874-882.
36. Matthews K, Schafer A, Pham A, Frieman MB. 2014. The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity. Virol J 11:209.
37. Li J, Sun W, Subrahmanyam PB, Page C, Younger KM, Tiper IV, Frieman MB, Kimball AS, Webb TJ. 2014. NKT Cell Responses to B Cell Lymphoma. Med Sci (Basel) 2:82-97.
38. Ladner JT, Beitzel B, Chain PS, Davenport MG, Donaldson EF, Frieman MB, Kugelman JR, Kuhn JH, O'Rear J, Sabeti PC, Wentworth DE, Wiley MR, Yu GY, Threat Characterization C, Sozhamannan S, Bradburne C, Palacios G. 2014. Standards for sequencing viral genomes in the era of high-throughput sequencing. MBio 5:e01360-01314.
39. Kim WK, Jain D, Sanchez MD, Koziol-White CJ, Matthews K, Ge MQ, Haczku A, Panettieri RA, Jr., Frieman MB, Lopez CB. 2014. Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. Am J Respir Crit Care Med 189:437-448.
40. Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, Olinger GG, Jr., Frieman MB, Holbrook MR, Jahrling PB, Hensley L. 2014. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 95:571-577.
41. Frieman MB. 2014. The art of war: battles between virus and host. Curr Opin Virol 6:76-77.
42. Enjuanes L, Sola I, Frieman MB. 2014. Virus Research. Nidoviruses I. Foreword. Virus Res 194:1-2.
43. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, Johnson RF, Olinger GG, Jr., Jahrling PB, Laidlaw M, Johansen LM, Lear-Rooney CM, Glass PJ, Hensley LE, Frieman MB. 2014. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 58:4885-4893.
44. Coleman CM, Matthews KL, Goicochea L, Frieman MB. 2014. Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J Gen Virol 95:408-412.
45. Coleman CM, Liu YV, Mu H, Taylor JK, Massare M, Flyer DC, Smith GE, Frieman MB. 2014. Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 32:3169-3174.
46. Coleman CM, Frieman MB. 2014. Coronaviruses: important emerging human pathogens. J Virol 88:5209-5212.
47. Taylor JK, Coleman CM, Postel S, Sisk JM, Bernbaum JG, Venkataraman T, Sundberg EJ, Frieman MB. 2015. Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference. J Virol 89:11820-11833.
48. Sisk JM, Frieman MB. 2015. Screening of FDA-Approved Drugs for Treatment of Emerging Pathogens. ACS Infect Dis 1:401-402.
49. Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, Hunt C, Strein J, Berrebi A, Sisk JM, Matthews KL, Babb R, Chen G, Lai KM, Huang TT, Olson W, Yancopoulos GD, Stahl N, Frieman MB*, Kyratsous CA*. 2015. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci U S A 112:8738-8743.
50. Nita-Lazar M, Banerjee A, Feng C, Amin MN, Frieman MB, Chen WH, Cross AS, Wang LX, Vasta GR. 2015. Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding. Mol Immunol 65:1-16.
51. Mojica SA, Hovis KM, Frieman MB, Tran B, Hsia RC, Ravel J, Jenkins-Houk C, Wilson KL, Bavoil PM. 2015. SINC, a type III secreted protein of Chlamydia psittaci, targets the inner nuclear membrane of infected cells and uninfected neighbors. Mol Biol Cell 26:1918-1934.
52. McSweegan E, Weaver SC, Lecuit M, Frieman MB, Morrison TE, Hrynkow S. 2015. The Global Virus Network: Challenging chikungunya. Antiviral Res 120:147-152.
53. Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, Traynor D, Johnson RF, Dyall J, Kuhn JH, Olinger GG, Hensley LE, Jahrling PB. 2015. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob Agents Chemother 59:1088-1099.
54. Gralinski LE, Ferris MT, Aylor DL, Whitmore AC, Green R, Frieman MB, Deming D, Menachery VD, Miller DR, Buus RJ, Bell TA, Churchill GA, Threadgill DW, Katze MG, McMillan L, Valdar W, Heise MT, Pardo-Manuel de Villena F, Baric RS. 2015. Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. PLoS Genet 11:e1005504.
55. Frieman MB, Sola I, Enjuanes L. 2015. Virus Research. Foreword. Nidoviruses II. Virus Res 202:1-2.
56. Coleman CM, Frieman MB. 2015. Growth and Quantification of MERS-CoV Infection. Curr Protoc Microbiol 37:15E 12 11-19.
57. Astry B, Venkatesha SH, Laurence A, Christensen-Quick A, Garzino-Demo A, Frieman MB, O'Shea JJ, Moudgil KD. 2015. Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ. Clin Immunol 157:228-238.
58. Coleman CM, Sisk JM, Mingo RM, Nelson EA, White JM, Frieman MB. 2016. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J Virol 90:8924-8933.
59. Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Matsushita H, Liu Y, Postnikova EN, Ork BL, Glenn G, Flyer D, Defang G, Raviprakash K, Kochel T, Wang J, Nie W, Smith G, Hensley LE, Olinger GG, Kuhn JH, Holbrook MR, Johnson RF, Perlman S, Sullivan E, Frieman MB. 2016. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med 8:326ra321.
60. Moser LA, Ramirez-Carvajal L, Puri V, Pauszek SJ, Matthews K, Dilley KA, Mullan C, McGraw J, Khayat M, Beeri K, Yee A, Dugan V, Heise MT, Frieman MB, Rodriguez LL, Bernard KA, Wentworth DE, Stockwell TB, Shabman RS. 2016. A Universal Next-Generation Sequencing Protocol To Generate Noninfectious Barcoded cDNA Libraries from High-Containment RNA Viruses. mSystems 1.
61. Wirblich C, Coleman CM, Kurup D, Abraham TS, Bernbaum JG, Jahrling PB, Hensley LE, Johnson RF, Frieman MB, Schnell MJ. 2017. One-Health: a Safe, Efficient, Dual-Use Vaccine for Humans and Animals against Middle East Respiratory Syndrome Coronavirus and Rabies Virus. J Virol 91.
62. Venkataraman T, Frieman MB. 2017. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis. Antiviral Res 143:142-150.
63. Venkataraman T, Coleman CM, Frieman MB. Overactive Epidermal Growth Factor Receptor Signaling Leads to Increased Fibrosis after Severe Acute Respiratory Syndrome Coronavirus Infection. J Virol. 2017 May 26;91(12). pii: e00182-17. doi:10.1128/JVI.00182-17. Print 2017 Jun 15. PubMed PMID: 28404843; PubMed Central PMCID: PMC5446658.
64. Dyall J, Gross R, Kindrachuk J, Johnson RF, Olinger GG, Jr., Hensley LE, Frieman MB, Jahrling PB. 2017. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs 77:1935-1966.
65. Coleman CM, Venkataraman T, Liu YV, Glenn GM, Smith GE, Flyer DC, Frieman MB. 2017. MERS-CoV spike nanoparticles protect mice from MERS-CoV infection. Vaccine 35:1586-1589.
66. Coleman CM, Sisk JM, Halasz G, Zhong J, Beck SE, Matthews KL, Venkataraman T, Rajagopalan S, Kyratsous CA, Frieman MB. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J Virol. 2016 Dec 16;91(1). pii: e01825-16.
67. Cong Y, Hart BJ, Gross R, Zhou H, Frieman MB, Bollinger L, Wada J, Hensley LE, Jahrling PB, Dyall J, Holbrook MR. 2018. MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells. PLoS One 13:e0194868.
68. Rao X, Deiuliis JA, Mihai G, Varghese J, Xia C, Frieman MB, Sztalryd C, Sun XJ, Quon MJ, Taylor SI, Rajagopalan S, Zhong J. 2018. Monocyte DPP4 Expression in Human Atherosclerosis Is Associated With Obesity and Dyslipidemia. Diabetes Care 41:e1-e3.
69. Sisk JM, Frieman MB, Machamer CE. 2018. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol 99:619-630.
Determinants of Host Response to Coronavirus Pathogenesis
We utilize novel mouse models of SARS-CoV and MERS-CoV to identify the host response to infection while identifying pathways and proteins that regulate the response. In the past we have identified STAT1, EGFR and other wound healing factors that regulate disease severity for SARS-CoV. After the emergence of MERS-CoV in 2012 we rapidly developed a mouse model for the virus and have been identifying the host factors and immune response to MERS-CoV infection. Wildtype mice are not permissive to MERS-CoV infection due to the an amino acid difference in the binding site of the MERS-CoV Spike protein with its cell surface receptor Dipeptidyl Peptidase IV (DPP4). We found that the mouse DPP4 does not bind MERS-CoV Spike but the human DPP4 does. We quickly realized that to study MERS-CoV pathogenesis in mice we would have to create a mouse that expressed human DPP4 instead of mouse DPP4. We rapidly produced and characterized a mouse that had human DPP4 knocked-in to the mouse DPP4 loci, replacing the gene but retaining the mouse DPP4 promoter. This allowed for the correct expression kinetics of the human DPP4 in the mice. We found that MERS-CoV infected these mice, produced significant lung pathology and induced a unique inflammatory response in the mice, different from that of SARS-CoV. Using this model, we have further focused on the effects of diabetic comorbidity on disease severity. The reason for focusing on diabetes is because of the patients that have lethal MERS-CoV infection, the vast majority have preexisting comorbidities, the largest of which is Type 2 diabetes (T2D). We have modeled T2D in our MERS-CoV mouse model by feeding the mice a high fat diet for 12 weeks and find that MERS-CoV infection induces a more severe disease in these mice compared to normal mice. The T2D mice have slower inflammatory cell infiltration, enhanced epithelial cell hyperplasia at sites of infection and a skewed immune response. We are currently investigating the role of the MERS-CoV receptor, DPP4, in the T2D response and how its activity effects the immune response to the virus. One striking difference is that Type 2 alveolar cells are infected immediately after inoculation in the diabetic mice, whereas they take 4 days after inoculation to become infected in normal mice. We believe that the Type 2 alveolar cells are more permissive in the diabetic mice to MERS-CoV due to a difference in accessibility of the virus to the cell surface and of a reduced innate immune response of these cells in diabetic mice. Mucus and surfactant levels are reduced on the surface of the alveoli in diabetic mice, allowing for increased virus deposition deep into the lungs, altering their microenvironment and enhancing infection. The same phenomenon will affect not just MERS-CoV but also other respiratory viruses including Influenza virus, bacterial infections including S. aureus and fungal infections including Aspergillus sp. We believe this model will be critical in the future for determining the role of diabetes and other comorbidities in the host response to MERS-CoV and potentially other pathogens.
In vitro modeling of coronavirus:host interactions
We develop a system to use S. cerevisiaeas a tool to identify host proteins and pathways critical for viral replication. Using my background in yeast genetics (PhD Thesis work at The Johns Hopkins University School of Medicine), we find that certain viral proteins expressed in yeast are able to induce a slow growth phenotype. This phenotype is remarkably useful for identifying suppressors/interactors of the pathways that the viral proteins effect, either directly or through their functional interactions with host proteins. We hypothesize that the function of viral proteins in cells will be conserved from mammalian cells to yeast and that these functions can be easily distinguished when the viral proteins are expressed singly rather than during a viral infection. Using a yeast based expression and suppressor screen platform, we have identified novel functional interactions for MERS-CoV and SARS-CoV proteins, as well as extending our screen to Influenza virus, Norovirus and Rotavirus. We are currently targeting these pathways with novel compounds to inhibit its function leading to increased IFN signaling and protection of cells from viral infection. We have used the same growth phenotype in yeast to identify novel anti-viral compounds for SARS-CoV, Influenza virus, MERS-CoV and Chikungunya virus that have been validated in vitro cell culture systems. Our studies are continuing to identify novel host proteins in mammalian cells via initial functional growth screens in yeast. These findings will be followed by in vivoanalysis using the mouse models developed in my laboratory.
Awards and Honors
1994-1997 HHMI Summer Research Fellowship to support research in the lab of Dr. Craig Pikaard (Washington Univ. in St. Louis)
1995-1997 HHMI Summer Research Travel Award (Wash Univ. in St. Louis)
2007 UNC-CH Post-Doctoral Award for Research Excellence
2007 ASV Post-Doctoral Travel Scholarship (UNC-CH)
2010,2012 Teaching Commendation for Host Defenses and Infectious Diseases (UMSOM)
2014 Winner, Daily Record, Innovator of the Year
Nominated for University of Maryland Research of the Year
2015-18 Teaching Commendation for Host Defenses and Infectious
Professional Society Memberships
2006-present Member of the American Society for Virology
2008-present Member of the American Society of Microbiology
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Experimental MERS Treatments Target Host Cell Receptor