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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Developing and Evaluating Animal Models for Studying the Safety and Efficacy of Vaccines Against Anthrax, Staphylococcal Infections, and Pertussis

Principal Investigator: Tod Merkel, PhD
Office / Division / Lab: OVRR / DBPAP / LRSP


General Overview

Our laboratory is studying the interaction between humans and three important bacterial pathogens, Bordetella pertussis (causes whooping cough), Bacillus anthracis (anthrax), and Staphylococcus aureus (causes skin disease, "blood poisoning," toxic shock syndrome). In order to gain a more complete understanding of these interactions, we identify and characterize the bacterial gene products that are required to establish infection and cause disease. In addition, we develop and use animal models and techniques for studying the immune system to identify and characterize the host immune response to the bacterial pathogens.

In order to help develop new vaccines and treatments for these diseases we are characterizing both the gene products that bacteria need to infect humans and the immune system responses that protect against disease. The new knowledge gained from our studies will help us to evaluate the efficacy of new vaccines to prevent--and drugs to treat--pertussis, staphylococcal diseases and anthrax.

Our expertise in the biology and pathogenesis (disease-causing mechanisms) of the organisms targeted by the products we regulate enables us to identify and define potential problems with these products, which we communicate to their developers and manufacturers. Indeed, we frequently can offer advice to these sponsors on how to address such concerns.

Since it is not possible to challenge human volunteers with anthrax toxin to test the efficacy of new anthrax vaccines, the approval of new anthrax vaccines will require extrapolating the results of tests in animals to humans. This will require us to develop a thorough understanding of the pathogenesis of B. anthracis in animal models of the disease, as well as the response of their immune system to anthrax infection.

Because advancements in our understanding of transmission of B. pertussis and disease progression is hindered by the lack of good animal models, our advances in aerosol biology and our animal model development promises to significantly advance our ability to develop and license new pertussis vaccines. In addition to contributing to scientific knowledge, our work in animal model development makes us aware of the practical hurdles involved in conducting these animal model studies. This knowledge will help us to evaluate data submitted by manufacturers of such vaccines as part of the FDA process of regulating these products.


Scientific Overview

We study the early steps of B. anthracis infection of the host and the role of the innate immune response in controlling the spread of pathogens during these stages of infection. The goals of our research are to 1) identify the components of the innate immune response that control of B. anthracis infection and the bacterial factors required for evading the innate immune response; and 2) characterize the interaction of the pathogen with the immune system. On a parallel track, we are developing a cost-effective mouse aerosol challenge model for screening candidate vaccines and therapeutics for the treatment of anthrax.

Our laboratory is also studying the regulation of the expression of Bordetella pertussis virulence factors by the two-component regulatory system encoded by the bvg locus The BvgS protein mediates the phosphorylation of BvgA, which upon phosphorylation activates transcription of B. pertussis virulence factors. In addition to the set of genes that is activated by the bvg locus, we identified bvgR, as the gene encoding the repressor of the bvg-repressed genes and risA as the gene encoding the activator of the bvg-repressed genes. Our group also recently demonstrated that the expression of the bvg-repressed genes enhances survival of B. pertussis in aerosols, thereby increasing the likelihood that a B. pertussis cell expelled from an infected host will survive long enough to be inhaled by a naive host.

Our results suggest that the bvg locus of B. pertussis mediates the transition between two environments: inside the host where the bvg-activated virulence factors are required, and outside the host where the bvg-repressed aerosol tolerance factors are required. Our ongoing work is focused on understanding transmission of B. pertussis and evaluating efficacy of pertussis vaccines in transmission and infection models.

We are also working to evaluate the ability of Staphylococcal aureus antigens to contribute to vaccine efficacy. Our goal is to identify antigens or combinations of antigens that confer protection against multiple forms of staphylococcal disease. My group is establishing systemic, implant, pulmonary, and skin models of staphylococcal infection. We will clone, express, and purify selected S. aureus antigens and use them to vaccinate groups of mice; then challenge each type of vaccinated animal model to determine the ability of each antigen to confer protection against these various S. aureus infections. This work will significantly advance public health efforts to develop effective vaccines that prevent staphylococcal disease.


Publications

Infect Immun 2013 Apr;81(4):1306-15
An Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections.
Prabhakara R, Foreman O, De Pascalis R, Lee GM, Plaut RD, Kim SY, Stibitz S, Elkins KL, Merkel TJ

PLoS One 2013 Apr 29;8(4):e63040
Evaluation of Genetically Inactivated Alpha Toxin for Protection in Multiple Mouse Models of Staphylococcus aureus Infection.
Brady RA, Mocca CP, Prabhakara R, Plaut RD, Shirtliff ME, Merkel TJ, Burns DL

PLoS One 2013;8(3):e59232
Stably Luminescent Staphylococcus aureus Clinical Strains for Use in Bioluminescent Imaging.
Plaut RD, Mocca CP, Prabhakara R, Merkel TJ, Stibitz S

Infect Immun 2012 Sep;80(9):3189-93
A dissemination bottleneck in murine inhalational anthrax.
Plaut RD, Kelly VK, Lee GM, Stibitz S, Merkel TJ

J Infect Dis 2012 Sep;206(6):902-6
Airborne Transmission of Bordetella pertussis.
Warfel JM, Beren J, Merkel TJ

PLoS One 2012;7(5):e37610
Moraxella catarrhalis Activates Murine Macrophages through Multiple Toll Like Receptors and Has Reduced Clearance in Lungs from TLR4 Mutant Mice.
Hassan F, Ren D, Zhang W, Merkel TJ, Gu XX

Infect Immun 2012 Apr;80(4):1530-6
Nonhuman primate model of pertussis.
Warfel JM, Beren J, Kelly VK, Lee G, Merkel TJ

J Immunol 2012 Feb 1;188(3):1469-78
Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice.
Banda NK, Hyatt S, Antonioli AH, White JT, Glogowska M, Takahashi K, Merkel TJ, Stahl GL, Mueller-Ortiz S, Wetsel R, Arend WP, Holers VM

Anal Chem 2011 Apr 1;83(7):2511-7
Peptide-based fluorescence resonance energy transfer protease substrates for the detection and diagnosis of bacillus species.
Kaman WE, Hulst AG, van Alphen PT, Roffel S, van der Schans MJ, Merkel T, van Belkum A, Bikker FJ

Infect Immun 2011 Jan;79(1):153-66
Role of purine biosynthesis in Bacillus anthracis pathogenesis and virulence.
Jenkins A, Cote C, Twenhafel N, Merkel T, Bozue J, Welkos S

Proc Natl Acad Sci U S A 2010 Oct 19;107(42):18091-6
Development of a highly efficacious vaccinia-based dual vaccine against smallpox and anthrax, two important bioterror entities.
Merkel TJ, Perera PY, Kelly VK, Verma A, Llewellyn ZN, Waldmann TA, Mosca JD, Perera LP

Infect Immun 2010 Jun;78(6):2418-28
Inflammatory cytokine response to Bacillus anthracis peptidoglycan requires phagocytosis and lysosomal trafficking.
Iyer JK, Khurana T, Langer M, West CM, Ballard JD, Metcalf JP, Merkel TJ, Coggeshall KM

Infect Immun 2009 Oct;77(10):4529-37
Nod1/Nod2-mediated recognition plays a critical role in induction of adaptive immunity to anthrax after aerosol exposure.
Loving CL, Osorio M, Kim YG, Nuñez G, Hughes MA, Merkel TJ

Infect Immun 2009 Apr;77(4):1475-82
Anthrax protective antigen delivered by Salmonella enterica serovar Typhi Ty21a protects mice from a lethal anthrax spore challenge.
Osorio M, Wu Y, Singh S, Merkel TJ, Bhattacharyya S, Blake MS, Kopecko DJ

Infect Immun 2009 Jan;77(1):255-65
Role of anthrax toxins in dissemination, disease progression, and induction of protective adaptive immunity in the mouse aerosol challenge model.
Loving CL, Khurana T, Osorio M, Lee GM, Kelly VK, Stibitz S, Merkel TJ

Infect Immun 2008 May;76(5):2177-82
Anamnestic Protective Immunity to Bacillus anthracis is Antibody-mediated but Independent of Complement and Fc Receptors.
Harvill ET, Osorio M, Loving CL, Lee GM, Kelly VK, Merkel TJ

Free Radic Res 2008 Jan;42(1):49-56
Spin labelling of Bacillus anthracis endospores: a model for in vivo tracking by EPR imaging.
Tsai P, Cao GL, Merkel TJ, Rosen GM

Infect Immun 2007 Jun;75(6):2689-98
A Murine Aerosol Challenge Model of Anthrax.
Loving CL, Kennett M, Lee GM, Grippe VK, Merkel TJ

Proc Natl Acad Sci U S A 2006 Dec 19;103(51):19272-7
A fully integrated microfluidic genetic analysis system with sample-in-answer-out capability.
Easley CJ, Karlinsey JM, Bienvenue JM, Legendre LA, Roper MG, Feldman SH, Hughes MA, Hewlett EL, Merkel TJ, Ferrance JP, Landers JP

Infect Immun 2005 Nov;73(11):7535-40
MyD88-dependent signaling contributes to protection following Bacillus anthracis spore challenge of mice: implications for Toll-like receptor signaling.
Hughes MA, Green CS, Lowchyj L, Lee GM, Grippe VK, Smith MF Jr, Huang LY, Harvill ET, Merkel TJ

Infect Immun 2005 Jul;73(7):4420-2
Complement depletion renders C57BL/6 mice sensitive to the Bacillus anthracis Sterne strain.
Harvill ET, Lee G, Grippe VK, Merkel TJ

J Bacteriol 2005 Mar;187(5):1648-58
Activation of the vrg6 Promoter of Bordetella pertussis by RisA.
Croinin TO, Grippe VK, Merkel TJ

Infect Immun 2004 Nov;72(11):6382-9
Cytokine response to infection with Bacillus anthracis spores.
Pickering AK, Osorio M, Lee GM, Grippe VK, Bray M, Merkel TJ

Infect Immun 2004 May;72(5):3069-72
Macrophages release tumor necrosis factor alpha and interleukin-12 in response to intracellular Bacillus anthracis spores.
Pickering AK, Merkel TJ

     
 

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