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R. Mark L. Buller, Ph.D.

 

Mark Buller, Ph.D.
Professor
Molecular Microbiology & Immunology
Saint Louis University School of Medicine

Education:
Ph.D., Institute of Virology, Glasgow, Scotland, 1976

Doisy Research Center
1100 South Grand Blvd
Office/Lab 725/745
Saint Louis, MO 63104

Email: bullerrm@slu.edu
Office: 977-8870
Lab:     977-8865


 

 R. Mark L. Buller, Ph.D.

R. Mark L. Buller, Ph.D. 

Research

Research in this laboratory revolves around the study of viral pathogenesis, the development of therapeutics for orthopoxvirus infections, and the diagnosis of microbial infections. Pathogenesis is an interplay of the genetic expression of the infecting agent and the host's responses to infection, with the dynamics dictating the severity and the outcome of the disease process. Our goal is to define the genetic basis for poxvirus virulence in the mouse (ectromelia virus) and humans (molluscum contagiosum virus; MCV), as well as the multifactorial host response to infection, which precedes recovery from disease. MCV has a world-wide distribution causing persistent, benign, skin tumors in children, sexually active adults and is an opportunistic infection of acquired immunodeficiency syndrome (AIDS) patients. The study of poxvirus pathogenesis has gained added importance with the proposed use of recombinant vaccinia viruses as vaccines for humans, domesticated animals and wild-life, and as therapeutics for the treatment of solid tumors.

We are currently involved in efficacy testing of anti-virals and vaccines against orthopoxviruses in small animal models. Although four orthopoxviruses have been shown to cause disease in humans, only vaccinia (VACV), cowpox (CPXV) and monkeypox virus (MPXV) still cause human infections. With the global eradication of the disease smallpox in 1979, the causative agent variola virus (VAR) no longer circulates in human populations; however, there is concern that VAR could be reintroduced through bioterrorism and/or biowarfare. The reintroduction of aerosolized VAR (or perhaps monkeypox virus) into human populations would result in high levels of mortality since an efficacious anti-viral therapy is not available for the treatment of exposed individuals. Also the routine immunization of the U.S. civil population with VAC had all but ceased in the early 1970's, resulting in the population under the age of 30 lacking cross-protective immunity to VAR. Furthermore, the strength of vaccine immunity in older Americans has decreased with the passage of time leaving these individuals with less than optimal protection against smallpox. And finally, a growing segment of the American population is immunocompromised as a result of infection with human immunodeficiency virus (HIV), and the use of immunosupressive drugs for treatment of cancer and prevention of the rejection of organ transplantations.

Cytokines are pivotal to a balanced innate or cell-mediated immune response, can be indicative of disease progression and/or resolution, and are being evaluated as therapeutics. There is a need to purify and/or to measure key cytokines rapidly with accuracy, precision and sensitivity. The current technology, which is based on antibodies, has a number of drawbacks. An alternative approach explored in our laboratory, is the use of pathogen-encoded cytokine-binding proteins. It is anticipated that pathogens have evolved binding proteins, antagonists and/or specific neutralizing phenotypes directed against key signaling and effector molecules involved in the multi-faceted host defense system. Thus by screening the genomes of a wide-range of microbial agents we would expect to find coding sequences for binding proteins for the most important cytokines. Consistent with this view is the identification of poxvirus genes encoding binding activities for TNF, type I and type II interferons (IFN), IL-1ß, IL-18 and ß-chemokines. As proof-of-concept, we have developed a sensitive assay for measuring both mouse and human IFN-? using the IFN-? binding protein encoded by the orthopoxvirus ectromelia.. A longer term goal is to develop an instrument based on this technology to measure rapidly cytokines indicative of disease. It is envisaged that such an instrument will be of great value in the stratification of patients for treatment, and the development of treatments, for sepsis.

Proposed modulation of Keratinocyte prolifteration and differentiation by MC131

A MCV-infected keratinocyte (molluscum body) filled with virions

The long-term goal of this research is to apply our knowledge concerning the host's responses to infection and the ectromelia virus and MCV hrm genes to construct improved poxvirus vectors for gene therapy and vaccine applications as well as the design of anti-viral therapies. Currently we are evaluating poxvirus vectors for cancer therapy and as a recombinant vaccine against HIV.

Mark Buller Lab
                                        Left to right:  Allyson Renthe, Scott Parker, Galyna Yakymechko, Mark Buller, Mary Weber,                                                   Ryan Crump, Konstantin Doronin, and Ed Hembrador

Publications

Oncolytic Viruses.
Chen NG, Szalay AA, Buller RM, Lauer UM.
Adv  Virol. 2012;2012:320206 Epub 2012 Jun 6.
PMID: 22754567

Mousepox, a small animal model of smallpox.
Esteban D, Parker S, Schriewer J, Hartzler, Buller RM.
Methods Mol Biol. 2012;890:177-98.
PMID:  22688768

Ccr5 regulates inflammatory gene expression in response to encephalomyocarditis virus infection.
Christmann BS, Moran JM, McGraw JA, Buller RM, Corbett JA.
Am J Pathol. 2011 Dec;179(6):2941-51 Epub 2011 Oct. 11J Virol. 2011 Aug 17;85(21):11170-82 Epub 2011 Aug 17.
PMID:  22001348

The Ectromelia Virus SPI-2 Protein Causes Lethal Mousepox by preventing NK Cell Responses.
Melo-Silva CR, Tscharke DC, Lobigs M, Koskinen A, Wong YC, Buller RM, Müllbacher A, Regner M.
J Virol. 2011 Aug 17;85(21):11170-82 Epub 2011 Aug 17.
Pubmed Abstract Link: 21849445

Poxvirus interleukin-4 expression overcomes inherent resistance and vaccine-induced immunity: pathogenesis, prophylaxis, and antiviral therapy.
Chen N, Bellone CJ, Schriewer J, Owens G, Fredrickson T, Parker S, Buller RM.
Virology. 2011 Jan 20;409(2):328-37. Epub 2010 Nov 10.
Pubmed Absctract Link: 21071055

VennVax, a DNA-prime, peptide-boost multi-T-cell epitope poxvirus vaccine, induces protective immunity against vaccinia infection by T cell response alone.
Moise L, Buller RM, Schriewer J, Lee J, Frey SE, Weiner DB, Martin W, De Groot AS.
Vaccine. 2011 Jan 10;29(3):501-11. Epub 2010 Nov 4.
Pubmed Abstract Link: 21055490

The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus.
Denzler, JL, Schriewer J, Parker S, Werner C, Hartzler H, Hembrador E, Huynh T, Holechek S, Buller RM, Jacobs BL.
Vaccine. 2011 Dec 6;29(52):9691-6 Epub 2011 Oct 5.
PMID:  21983358

Ectromelia virus infections of mice as a model to support the licensure of anti-orthopoxvirus therapeutics.
Parker A, Siddiqui AM, Painter G, Schriewer J, Buller RM.
Viruses. 2010 Sep;2(9):1918-32 Epub 2010 Sep 3.
PMID:  21994714

Ectromelia virus inhibitor of complement enzymes protects intracellular mature virus and infected cells from mouse complement.
Moulton EA, Bertram P, Chen N, Buller RM, Atkinson JP.
J Virol. 2010 Sep;84(18):9128-39. Epub 2010 Jul 7.
Pubmed Abstract Link: 20610727

Multiple phosphatidylinositol 3-kinases regulate vaccinia virus morphogenesis.
McNulty S, Bornmann W, Schriewer J, Werner C, Smith SK, Olson VA, Damon IK, Buller RM, Heuser J, Kalman D.
PLoS One. 2010 May 28;5(5):e10884.
Pubmed Abstract Link: 20526370

Src family kinases participate in the regulation of encephalomyocarditis virus-induced cyclooxygenase-2 expression by macrophages.
Freudenburg W, Buller RM, Corbett JA.
J Gen Virol. 2010 Sep;91(Pt 9):2278-85. Epub 2010 May 26.
Pubmed Abstract Link: 20505008

Phosphatidylinositol 3-kinase regulates macrophage responses to double-stranded RNA and encephalomyocarditis virus.
Freudenburg W, Moran JM, Lents NH, Baldassare JJ, Buller RM, Corbett JA.
J Innate Immun. 2009 Dec;2(1):77-86. Epub 2009 Oct 1.
Pubmed Abstract Link: 20375625

A mouse model of lethal infection for evaluating prophylactics and therapeutics against Monkeypox virus.
Stabenow J, Buller RM, Schriewer J, West C, Sagartz JE, Parker S.
J Virol. 2010 Apr;84(8):3909-20. Epub 2010 Feb 3.
Pubmed Abstract Link: 20130052

Antiviral evaluation of octadecyloxyethyl esters of (S)-3-hydroxy-2-(phosphonomethoxy)propyl nucleosides against herpesviruses and orthopoxviruses.
Valiaeva N, Prichard MN, Buller RM, Beadle JR, Hartline CB, Keith KA, Schriewer J, Trahan J, Hostetler KY.
Antiviral Res. 2009 Dec;84(3):254-9. Epub 2009 Oct 1.
Pubmed Abstract Link: 19800369

Therapeutic and prophylactic drugs to treat orthopoxvirus infections.
Parker S, Handley L, Buller RM.
Future Virol. 2008 Nov;3(6):595-612.
Pubmed Abstract Link: 19727418

The new ACAM2000 vaccine and other therapies to control orthopoxvirus outbreaks and bioterror attacks.
Handley L, Buller RM, Frey SE, Bellone C, Parker S.
Expert Rev Vaccines. 2009 Jul;8(7):841-50. Review.
Pubmed Abstract Link: 19538111

Surviving mousepox infection requires the complement system.
Moulton EA, Atkinson JP, Buller RM.
PLoS Pathog. 2008 Dec;4(12):e1000249. Epub 2008 Dec 26.
Pubmed Abstract Link: 19112490

Mousepox in the C57BL/6 strain provides an improved model for evaluating anti-poxvirus therapies.
Parker S, Siddiqui AM, Oberle C, Hembrador E, Lanier R, Painter G, Robertson A, Buller RM.
Virology. 2009 Mar 1;385(1):11-21. Epub 2008 Dec 18.
Pubmed Abstract Link: 19100593

Using biomarkers to stage disease progression in a lethal mousepox model treated with CMX001.
Parker S, Schriewer J, Oberle C, Robertson A, Lanier R, Painter G, Buller RM.
Antivir Ther. 2008;13(7):863-73.
Pubmed Abstract Link: 19043920

Experimental infection of an African dormouse (Graphiurus kelleni) with monkeypox virus.
Schultz DA, Sagartz JE, Huso DL, Buller RM.
Virology. 2009 Jan 5;383(1):86-92. Epub 2008 Nov 1.
Pubmed Abstract Link: 18977501

Fodil-Cornu N, Lee SH, Belanger S, Makrigiannis AP, Biron CA, Buller RM, Vidal SM.
Ly49h-deficient C57BL/6 mice: a new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex.
J Immunol. 2008 Nov 1;181(9):6394-405.
Pubmed Abstract Link: 18941230

Schaecher SR, Stabenow J, Oberle C, Schriewer J, Buller RM, Sagartz JE, Pekosz A.
An immunosuppressed Syrian golden hamster model for SARS-CoV infection.
Virology. 2008 Oct 25;380(2):312-21.
Pubmed Abstract Link: 18760437

Toth K, Spencer JF, Dhar D, Sagartz JE, Buller RM, Painter GR, Wold WS.
Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model.
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7293-7.
Pubmed Abstract Link: 18490659

Parker AK, Yokoyama WM, Corbett JA, Chen N, Buller RM.
Primary naive and interleukin-2-activated natural killer cells do not support efficient ectromelia virus replication.
J Gen Virol. 2008 Mar;89(Pt 3):751-9.
Pubmed Abstract Link: 18272767

Nuara AA, Walter LJ, Logsdon NJ, Yoon SI, Jones BC, Schriewer JM, Buller RM, Walter MR.
Structure and mechanism of IFN-gamma antagonism by an orthopoxvirus IFN-gamma-binding protein.
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1861-6.
Pubmed Abstract Link: 18252829

 

Grants

Current

NIAID Contract No. HHSN272201000021 (PI)   09/27/10-09/26/13
NIH NIAID
Rodent Models for Human Adenoviruses
The goals of the project are to use our Syrian hamster model to evaluate potential drugs that inhibit human adenovirus replication following intravenous or respiratory infection.

NIAID Contract No. HHSN272201000021 (PI)   09/30/11-08/31/13
NIH NIAID
Mouse Models for Orthopoxviruses
The goals of the project are to use our mouse models to evaluate potential drugs that inhibit orthopoxvirus replication following respiratory infection.

1U54 AI057160-01 (CO-PI) 03/01/09-02/28/14 
NIH/NIAID/MRCE (Core D)
Midwest Regional Centers of Excellence for Biodefense and Emerging Infectious Disease Research (MRCE)
The goal of our portion of the Center grant is to provide small animal model development for NIAID category A agents especially variola virus and yersinia pestis.  We will focus on developing respiratory infection models for basic research and for testing of anti-microbials and vaccines.

2012-12062800004 (PI) 08/16/12-08/15/14 
Central Intelligence Agency
Immunological Profiling to Distinguish Virus (Monkeypox) Infection from (Smallpox) Vaccination
The goals of the project are to use T cell receptor profiling to distinguish between humans exposed to a pathogen and immunized with with the corresponding vaccine.  

HDTRA1-12C-0051 (CO-PI) 08/27/12-08/26/15 
Defense Threat Reduction Agency
Multi-pathogen Antiviral Medical Countermeasure Deploying FDA Approved Drug
The goals of the project are to use our CAST/EiJ mouse model and monkeypox virus to evaluate the repurposing of the licensed drugs Gleevac and Tasigna for the treatment of human orthoposvirus infections.

Completed

5R01 AI074057-02 (CO-PI) 04/15/08-03/31/13
NIH/NIAID/Veterans Medical Research Foundation of San Diego
Optimization of HPMPA and CDV Analogs for Treatment Smallpox Infection
To screen candidate compounds for anti-poxvirus activity in vitro and in vivo in the mousepox model.

1R01 A1072462 (CO-PI) 03/01/08-02/28/13
NIH/NIAID/Emory
Inhibitors of Poxvirus Motility and Release
To evaluate the efficacy of candidate compounds against the entry and egress of orthopoxviruses.

R21 AI083693 (CO-PI) 09/01/09-08/31/12
NIH/NIAID/Case Western Reserve
Mucosal Innate Immune Defense to Rift Valley Fever Virus
To characterize the role of Toll-like receptors in the innate response to mucosal infections with Rift Valley Fever Virus.

R21 A0178800 (CO-PI)     09/17/09-08/31/11 
NIH/NIAID/EpiVax
Optimization of HIV Vaccine Subunit Delivery
To optimize the composition and delivery of a HIV subunit recombinant vaccine using a vaccine virus challenge system

N01 AI30063 Task Order C24 (CO-PI) 09/01/07-05/31/11

NIH/NIAID/Southern Research
Mouse Models for Orthopoxviruses
The goal is to test vaccines and antivirals against smallpox in small animal model.

N01-AI-15436 (PI) 05/01/01-04/30/08
NIH/NIAID
Small Animal Models of human Orthopoxvirus Infections for Evaluation of Experimental Therapies
To test antivirals against orthopoxviruses virulent for mice and rabbits.

R01 AI44458 (Co-investigator) 09/30/98-05/31/06
NIH/NIAID
Mechanisms of Virus-induced Beta Cell Damage
The major goal of this project is to study the viral induction of insulin dependent diabetes mellitus. Dr. Buller will provide expertise on the various viruses that are used in the project.

U01 AI-54694 (Co-investigator) 03/15/03-02/29/05
NIH/NIAID
Contract to Elusys
Heteropolymer System to treat vaccinia complications
The broad long-term objective of the project is to develop bispecific antibodies (Heteroploymers) for treatment of complications associated with the administration of smallpox vaccine.

U01 AI-057233 (Co-investigator) 09/01/03-02/28/08
NIH/NIAID Contract to Chimerix
Development of an oral drug for smallpox treatment
The major goal is to develop preclinical data, a GMP production facility, and carryout phase 1 and phase 2 testing for prodrugs based on cidofovir.

U54 AI-057160 (Core Director)(WU Sub-contract) 09/04/03-02/29/08
NIH/NIAID
Midwest Regional Centers of Excellence for Biodefense and Emerging Infectious Disease Research (MRCE)
The goal of our portion of the Center grant is to provide small animal model development for NIAID category A agents especially variola virus and yersinia pestis. We will focus on developing respiratory infection models for basic research and for testing of anti-microbials and vaccines.

R03-AI053718-01 (Juniata College Sub-Contract) 08/15/03-07/31/05
NIH/NIAID
Immunoproteomics and detection of viral disease
The long term goal is to detect early markers of virus infection.

R21-AI061512-01 (PI) 07/01/04-06/30/06
NIH/NIAID
Study of monkeypox virus in rodents
The goal of the project is to develop a small animal model to study monkeypox virus pathogenesis. The model may have utility for the study of the efficacy of antivirals and vaccines against smallpox and human monkeypox.

U01 AI-48653 (PI) 09/27/00-08/31/04
NIAID
Orthopoxvirus Genomics and Bioinformatics Resource Center
To construct a resource center for data and reagents that will facilitate the development of improved vaccines and anti-virals against human orthopoxvirus infections.

R21 AI-53346 (PI) 09/01/02-08/31/04
NIH/NIAID
Immunodominant epitopes of a smallpox vaccine in humans
The major goal of this project is to identify the viral protein epitopes recognized by the human immune system.


Subcontract to Acambis (Co-investigator) 03/01/01- 02/28/02
CDC
Comparison of the Dryvax Calf Lymph and OraVax Tissue Culture NYCBH Strains of vaccinia Virus
Using various approaches the disease potential of the current smallpox vaccine, Dryvax, was compared to the candidate replacement, the OraVax vaccine.

2 R42 AI42431-02A1 (PI) 08/01/00-12/28/02
NIAID (STTR) Program
Virus cytokine binding proteins in rapid cytokine assays.
The major goal of this project was the development of new assays for cytokine detection.