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Matthew B. Frieman

Matthew B. Frieman Ph.D.

Academic Title: Associate Professor
Primary Appointment: Microbiology and Immunology
Location: BRB, 3-020
Phone: (410) 706-2539
Lab: 410-706-2538

Personal History:

I completed my undergraduate studies at Washington University in St. Louis with a major in Biology. During my time there I worked in the lab of Dr. Craig Pikaard investigating chromatin silencing and gene expression. I then received my PhD from The Johns Hopkins University where I was mentored by Dr. Brendan Cormack in the Department of Molecular Biology and Genetics. There I studied the yeast cell wall and how cell wall proteins affect pathogenesis of Candida glabrata. My post-doctoral training was at The University of North Carolina at Chapel Hill in the laboratory of Dr. Ralph Baric where I studied the Innate Immune Response to the SARS Coronavirus. After my post-doctoral fellowship I joined the faculty in The Department of Microbiology and Immunology at The University of Maryland School of Medicine where I began my own lab in July of 2009. My lab mainly focuses on the Pathogenesis and Host Response of the SARS Coronavirus.

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Research Interests:

The emergence of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003 put a spotlight on emerging infectious diseases worldwide. While these new pathogens attempt to infect us, our bodies have many basic defenses to thwart their attacks. My lab investigates the interaction between the SARS-CoV and the host during infection. In the case of SARS-CoV and other highly pathogenic respiratory viruses, while the virus causes much damage to the lungs during infection, it is the body's response to the infections that lead to the most damage. My lab studies the interaction of SARS-CoV with the innate immune system, the host's response to viral infection and the pathways that after infection cause lung damage leading to acute lung injury (ALI), pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS).

SARS-CoV and the Innate Immune Response

Many highly pathogenic viruses interact directly with the innate immune response during infection. The innate immune system is the first line of defense against invading pathogens. Unlike the Adaptive Immune response that uses antibodies specific to the target, the innate immune response offers broad-spectrum protection against viruses and bacteria. Once the body senses the invading virus a signaling pathway is activated leading to the expression of hundreds of proteins to quench the replicating pathogen. We found that SARS-CoV blocks the induction of this anti-viral pathway, specifically the Interferon activation (RIG-I, IRF3, NFkB) and Interferon signaling pathway (STAT1). We have identified several proteins in SARS-CoV that inhibit either the activation, signaling, or nuclear transport of host proteins responsible for inducing the innate immune response. We are currently identifying the mechanism of action of these proteins and their roles in pathogenesis.

SARS-CoV and the Induction of Acute Lung Disease

The interaction of SARS-CoV and the host is highly regulated. The Spike protein on the surface of the SARS-CoV binds to ACE2 on the surface of airway epithelial cells. Once bound, the virus is endocytoced into endosomes and released into the cytoplasm where it starts its replication. As virus replicates and begins to traffic out of the cells into the surrounding milieu, the infected cells start to die. During this whole process the immune system begins to respond to the viral infection by recruiting inflammatory cells such as neutrophils, eosinophils, macrophages and dendritic cells to the site of infection. The SARS-CoV causes damage not only to the cells it infects but by manipulating the immune response so that the infiltrating cells also cause excessive damage to the tissue around the infection. This leads to the induction of a wound healing response and the recruitment of fibroblasts to repair the damaged tissue leading to more recruitment of inflammatory cells.

The pathways controlling the healing process, mainly controlled by the Epithelial Growth Factor Receptor (EGFR), are critical to survival from SARS. If the infection can be controlled and these pathways function correctly then the person survives, however if they become uncontrolled and the response leads to increased damage then the person may die. This damage does not always lead to immediate death. The repair process leaves severe scarring behind in humans and in mouse models of SARS-CoV which can cause death up to 2 years later in infected people. We are utilizing the mouse model of severe SARS-CoV infection to understand the role that the host response plays in the lethality of SARS-CoV.

Bats and emerging human viruses

Bats are among the most ancient and diverse mammals and have been implicated as the key reservoir species for several emerging and reemerging human viruses, like Ebola, Marburg, Severe Acute Respiratory Syndrome (SARS-CoV), Rabies (RABV), Hendra, and Nipah viruses. However, bats also harbor viral diseases more commonly associated with rodent reservoirs. In fact, Arenavirus, Bunyavirus, Flavivirus and Alphavirus are commonly harvested from bats globally, suggesting that bats may function as spillover reservoirs, augmenting the geographic dissemination of many common vector borne viruses that are typically maintained in reservoir pools like rodents and birds. These observations strongly argue that bats play a critical role in harboring and disseminating zoonotic-human viruses across the species barrier.

Using a multidisciplinary approach that includes bat ecologists, computational biologists, state of the art deep sequencing methodologies, and synthetic molecular genetics; our long-term goal is to detect, identify, and characterize the viromes of different bat species, and determine the viral and host factors that that facilitate cross-species transmission of these viruses to human and animal populations. We are going to identify and characterize the RNA virome of at least seven eastern North American bat species, evaluate the role of bats as reservoir hosts for common emerging viruses, develop a panel of select bat orthologous receptors and synthetic viral genomes that will facilitate research in the area of recovery, cultivation and trans-mammalian transmission.

Novel emerging Beta Coronavirus

A novel Coronavirus has recently emerged in the Middle East causing 17 known infections and 11 deaths. This new Coronavirus, named hCoV-EMC for Erasmus Medical College where the initial isolate was sequenced, is a beta Coronavirus that is phylogenetically similar to two bat Coronaviruses, BtCoV-HKU4 and BtCoV-HKU5. BtCoV-HKU4 and BtCoV-HKU5 were sequenced from bats in China however no viral isolates have been recovered from animals. These 3 viruses are also phylogenetically related to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) which also emerged from a bat reservoir in China causing severe respiratory illness and death in ~10% of the ~8000 infected individuals. Patients infected with hCoV-EMC present with severe respiratory illness, renal failure and, in greater than 50% of cases, this resulted in death. We are currently studying the ways that hCoV-EMC, BtCoV-HKU4 and BtCoV-HKU5 viral proteins interact with the innate immune response, the host response to infection and the identification of novel therapeutics for treatment of hCoV-EMC infection.

Grants and Contracts:

Current Support

“Role of the Epithelial Growth Factor Receptor in SARS Coronavirus Pathogenesis”
$250,000/year direct costs

Rocky Mountain Research Center of Excellence (RMRCE)
“Identification of Anti-viral compounds against Chikungunya Virus”
Role: Co-PI (with Thomas Morrison at U of Colorado, Denver)
$80,000/year (total costs)

Past Support

Southeast Research Center of Excellence Developmental Grant
“Metagenomic analysis of the virome of Eastern N. American Bats”
Role:Co-PI (with Eric Donaldson at U of N. Carolina, Chapel Hill)
$100,000/year (total costs)

K22 NIH/NIAID Research Scholar Development Award
Role: PI
$250,000 (total direct costs)

“Yeast based assays for chemical screens against SARS-CoV targets”
Role:Co-PI (with Daniel Engel, U of Virginia)
$125,000 (direct costs)

NRSA Post-doctoral Fellowship


Full list of papers on PubMed.

Page C, Goicochea L, Matthews K, Zhang Y, Klover P, Holtzman M, Hennighausen L, and Frieman M. Induction of alternatively activated macrophages enhances pathogenesis during SARS Coronavirus infection. Journal of Virology, 2012, Dec:86(24):13334-49.

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. Evidence Supporting a Zoonotic Origin of Human Coronavirus Strain NL63. J Virol. 2012 Dec;86(23):12816-25.

Frieman M, Basu D, Matthews K, Taylor J, Jones G, Pickles R, Baric R and Engel D. Yeast Based Small Molecule Screen for Inhibitors of SARS-CoV. PLoS One. 2011;6(12):e28479. Epub 2011 Dec 2.

Frieman M, Yount B, Agnihothram S, Page C, Donaldson E, Roberts A, Vogel L, Smock S, Scorpio D, Subbarao K, and Baric R. Molecular Determinants of SARS Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease. J Virol. 2012 Jan;86(2):884-97. Epub 2011 Nov 9.

Chen W, Toapanta F, Shirey K, Zhang L, Giannelou A, Page C, Frieman MB, Vogel S, Cross AS. Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza. Immunol Lett. 2012 Jan 30;141(2):227-34.

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, Pardo-Manuel de Villena F, Churchill GA. Genetic analysis of complex traits in the emerging collaborative cross. Genome Res. 2011 Aug;21(8):1213-22.

Peng X, Gralinski L, Ferris M, Frieman M, Thomas M, Proll S, Korth M, Heise M, Luo S, Schroth G, Tumpey T, Baric R & Katze M. Integrative deep sequencing of the mouse lung transcriptome reveals differential expression of diverse classes of small RNAs in response to respiratory virus infection. MBio. 2010 Oct 26;1(5).

Peng X, Gralinski L, Armour C, Ferris M, Thomas M, Proll S, Bradel-Tretheway B, Korth M, Castle J, Biery M, Bouzek H, Haynor D, Frieman M, Heise M, Raymond C, Baric R and Katze M. Unique signatures of long non-coding RNA expression in response to virus infection and altered innate immune signaling. MBio. 2010 Oct 26;1(5).

Donaldson E, Haskew A, Gates JE, Huynh J, Moore C, Frieman M. Metagenomic analysis of the Virome of three North American Bat Species : Viral Diversity between Different Bat Species that Share a Common Habitat. Journal of Virology, Dec 2010;84(24):13004-18.

Ortiz-Alcantara J, Bhardwaj K, Palaninathan S, Frieman M, Baric RS, and Kao CC. Small molecule inhibitors of the SARS-CoV NSP15 endoribonuclease. Virus Adaptation and Treatment. 2010:2 1-9.

Zornester* GA, Frieman* MB, Rosenzweig E, Korth MJ, Page C, Baric RS and Katze MG. Transcriptomic analysis reveals a mechanism for a pre-fibrotic phenotype in STAT1 knockout mice during SARS Coronavirus infection. Journal of Virology, 2010 Aug 11. PMID: 20702617. *co-first author.

Frieman MB, Chen J, Morrison TE, Whitmore A, Funkhouser W, Ward JM, Lamirande EW, Roberts A, Heise M, Subbarao K, Baric RS. SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog. 2010 Apr 8;6(4). PMID: 20386712.

Rockx B, Donaldson E, Frieman MB, Sheahan T, Corti D, Lanzavecchia A, Baric RS. Escape from human monoclonal antibody neutralization affects in vitro and in vivo fitness of severe acute respiratory syndrome coronavirus. J Infect Dis. 2010 Mar 15;201(6):946-55. PMID: 20144042

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. The ORF3a protein of SARS-CoV Promotes Membrane Rearrangement and Cell Death. J Virol. 2009 Nov 4. PMID: 19889773.

Day CW, Baric R, Cai SX, Frieman MB, Kumaki Y, Morrey JD, Smee DF, Barnard DL. A new mouse adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology. 2009 Oct 21. PMID: 19853271

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. Early Upregulation of ARDS Associated Cytokines Promote Lethal Disease in an Aged Mouse Model of SARS-CoV Infection. Journal of Virology, July 2009. PMID 19420084.

Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. SARS Coronavirus Papain-Like Protease Ubiquitin-like domain and Catalytic domain regulate antagonism of IRF3 and NFkB signaling. J Virol. 2009 July. PMID 19369340.

Frieman MB and Baric R. Mechanisms of SARS Pathogenesis and Innate Immune Modulation. MMBR.. Microbiol Mol Biol Rev. 2008 Dec;72(4):672-85. PMID 19052324.

Basu D, Walkiewicz MP, Frieman M, Baric RS, Auble DT, Engel DA. Novel influenza virus NS1 antagonists block replication and restore innate immune function. J Virol. 2009 Feb;83(4):1881-91. PMID 19052087.

Zupancic ML, Frieman M, Smith D, Alvarez RA, Cummings RD, Cormack BP. Glycan microarray analysis of Candida glabrata adhesin ligand specificity. Mol Microbiol. 2008 May;68(3):547-59. PMID 18394144.

Wathelet W, Frieman MB, and Baric R. The SARS coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol. 2007 Nov;81(21):11620-33. PMID 17715225.

Frieman MB, Yount B, Heise M, Davis N, Kopecky-Bromberg S, Johnston R, Palese P and Baric R. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 2007 Sep;81(18):9812-24. PMID 17596301.

Frieman, MB, Heise, M., and Baric RS. SARS Coronavirus and Innate Immunity. Virus Research. 2008 Apr;133(1):101-12. PMID 17451827.

Kopecky-Bromberg SA, Martinez-Sobrido L, Frieman M, Baric RS, Palese P. SARS Coronavirus Proteins ORF 3b, ORF 6 and Nucleocapsid Function as Interferon Antagonists. J Virol. 2006 Nov 15. PMID 17108024.

Baric RS, Sheahan T, Deming D, Donaldson E, Yount B, Sims AC, Roberts RS, Frieman MB, Rockx B. SARS coronavirus vaccine development. Adv Exp Med Biol. 2006;581:553-60. PMID 17037597.

Frieman MB, Yount B, Sims AC, Deming DJ, Morrison TE, Sparks J, Denison M, Heise M, Baric RS. SARS coronavirus accessory ORFs encode luxury functions. Adv Exp Med Biol. 2006;581:149-52. PMID 16282490.

Yount B, Roberts RS, Sims AC, Deming D, Frieman MB, Sparks J, Denison MR, Davis N, Baric RS. Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice. Journal of Virology. 2005 Dec;79(23):14909-22. PMID 16282490.

Frieman MB, Cormack BP. Multiple sequence signals determine the distribution of glycosylphosphatidylinositol proteins between the plasma membrane and cell wall in Saccharomyces cerevisiae. Microbiology 150: 3105-3114. PMID 15470092.

Frieman MB, Cormack BP. The omega site sequence of GPI-anchored proteins in S. cerevisiae can determine distribution between the membrane and the cell wall. Molecular Microbiology. 2003 Nov; 50(3): 883-896. PMID 14617149.

Frieman MB, McCaffery JM, Cormack BP. Modular domain structure in the Candida glabrata adhesin Epa1p, a beta1,6 glucan-cross-linked cell wall protein. Molecular Microbiology. 2002 Oct; 46(2):479-92. PMID 12406223.

Strichman-Almashanu LZ, Lee RS, Onyango PO, Perlman E, Flam F, Frieman MB, Feinberg AP. A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome Research. 2002 Apr;12(4):543-54. PMID 11932239.

Frieman M, Chen ZJ, Saez-Vasquez J, Shen LA, Pikaard CS. RNA polymerase I transcription in a Brassica interspecific hybrid and its progenitors: Tests of transcription factor involvement in nucleolar dominance. Genetics. 1999 May;152(1):451-60. PMID 10224274.