James E. Samuel, Ph.D.
Professor and Chair8447 State Hwy 47
Medical Research & Education Building, Room #3112
Bryan, TX 77807
Laboratory Phone: 979-436-0367
Office Phone: 979-436-0349
B.A. Miami University (Ohio) - 1976
M.S. Washington State University - 1983
Ph.D. Washington State University - 1986
Molecular Pathogenesis of Coxiella burnetii, the agent of Q fever
My laboratory works with the obligate intracellular bacterial pathogen, Coxiella burnetii, the etiologic agent of Q fever and a category B biothreat agent. The long-term goal of this research is to understand the molecular pathogenic mechanisms involved in the host-pathogen interaction. To accomplish this broad goal, project in the lab are designed to test the molecular mechanisms employed by both the host and pathogen. Current pathogen studies include 1) characterize the role of oxidative and nitrosative damage elicited by the host and mechanisms the organism employs to tolerate these environmental challenges 2) determine the critical mechanisms for iron acquisition encoded by the organism (primarily components of a Fur regulon), and 3) definition of the relative virulence of phylogenetically distinct isolate groups.
These studies have allowed the development of a more refined model of host-pathogen interactions and mechanisms used for survival and pathogenesis. C. burnetii depend on various strategies to down-regulate the normal host response to bacterial infection. Because of their obligate intracellular growth restriction, they have become exquisitely adapted to their specific niche, which is similar to a typical terminal phagolysosome that evolves into a large, replicative vacuole. The organism is extremely sensitive to oxidative stress, lacking several repair genes essential to mitigate oxidative DNA damage, has a reduce requirement for and uptake systems for acquisition of iron, and actively inhibits activation of an oxidative burst by phagocytic cells through the secretion of an acid phosphatase. Isolates that originate from acute Q fever patients are able to induce acute, atypical pneumonia in rodent challenge models while isolates from chronic Q fevers patients (most commonly endocarditis and hepatitis) do not cause acute disease in animal models, confirming distinct pathotype virulence potentials between isolate groups.
A particularly new and exciting area of research in the lab has been provided by our recent genome sequencing of several of these distinct pathotype isolates. These comparisons provide a selection of novel genes, especially those encoding proteins secreted by either type II or type IV systems which might mediate the unique virulence phenotypes (Figure 1).
Figure 1. Comparative genome analysis of C. burnetii Open Reading Frames (ORF) between newly sequenced isolates, noting the conserved and novel gene content of chromosome and plasmid (Beare et al. Manuscript Submitted).
Vaccine and Diagnostic Development
These current studies are focused on 1) the response to infection by the host, especially by cells of the immune system, 2) understanding the components of protective immunity elicited by a whole killed cellular antigen and, 3) identify appropriate recombinant vaccine strategies to elicit protective immunity. Protection against Q fever can be induced by vaccination with whole killed virulent organisms (WCV-1). Yet, due to the adverse reaction to vaccination of previously sensitized individuals, wide use of the vaccine has not been employed and no Q fever vaccine is available in the US. Hence, our efforts have been to develop a new generation of subunit vaccines. Our recent studies demonstrated that antibody against the O side chain polysaccharide of C. burnetii LPS is an important component of vaccine-induced immunity. Additionally, control of infection by vaccinates involves the ability to stimulate recall responses to antigen by memory T cells that activate interferon gamma-mediated killing by host macrophages. Therefore, we are identifying both dominant antigens for CD4+ T cells and methods the express O side chain on a heterologous carrier molecule as novel vaccine strategies.
To address these and other research questions, we have developed a variety of national and international collaborations. Two important collaborative opportunities critical for the success ofour studies are close interaction with investigators at the NIAID intramural facility, Laboratory of Intracellular Pathogens, Rocky Mountain Lab, and the Western Regional Center of Excellence with a network of core resource support.
Current Laboratory Members:
Laura Hendrix, Ph.D.
Erin Van Schaik
Mertens, K., L. Lantsheer, D.G. Ennis, and J.E. Samuel. Constitutive SOS expression and damage-inducibleAddAB-mediated recombinational repair systems for Coxiella burnetii as potential adaptations for survival within macrophages. 2008. Mol. Microbiol. In Press.
Briggs, H., N. Pul, R. Seshadri, M.J. Wilson, C. Tersteeg, K.E. Russell-Lodrique, M. Andoh, A.J. Baumler, and J.E. Samuel. A limited role for iron regulated genes in Coxiella burnetii pathogenesis. 2008. Infect. Immun. 76:2189-2201.
Zhang, G.Q., K.E. Russell-Lodrique, M. Andoh, Y. Zhang, L.R. Hendrix, J.E. Samuel. Mechanisms of vaccine-induced protective immunity against Coxiella burnetii infection in BALB/c mice. 2007. J. Immunol. 179:8372-8380.
Andoh, M., G. Zhang, K.E. Russell-Lodrigue, H. R. Shive, B.R. Weeks, and J.E. Samuel. T cells are essential for bacterial clearance, and gamma interferon, tumor necrosis factor alpha, and B cells are crucial for disease development in Coxiella burnetii infection in mice. 2007. Infect. Immun. 75. 3245-3255.
Coleman, S.A, E.R. Fischer, D.C. Cockrell, D.E. Voth, D. Howe, D.J. Mead, J.E. Samuel and B.A. Heinzen. Proteome and antigen profiling of Coxiella burnetii developmental forms. 2007. Infect Immun. 75: 290-298.
Russell-Lodrigue, K.E., D.N. McMurray, and J.E. Samuel. Clinical and pathologic changes in a guinea pig aerosol-challenge model of acute Q fever. 2006. Infect. Immun.74:6085-6091.
Beare, P.A., J.E. Samuel, D. Howe, K. Vitaneva, S.F. Porcella, and R.A. Heinzen. Genetic diversity of the Q fever agent, Coxiella burnetii, assessed by microarray-based whole-genome comparisons. 2006. J. Bacteriol. 188: 2309-2324.
Zhang, G.Q., H. To, K.E. Russell, L.R. Hendrix, T. Yamaguchi, H.Fukushi, K. Hirai, and J.E. Samuel. Identification and characterization of an immunodominant 28 Kilodalton Coxiella burnetii outer membrane protein specific to isolates associated with acute disease. 2005. Infect. Immun. 73: 1610-1617.
Zhang, G., K. Kiss, R. Seshadri, L.R. Hendrix, J.E. Samuel. Identification and cloning of immunodominant antigens of Coxiella burnetii. Infect. Immun. 2004. 72:844-852.
Brennan, R. K. Russell, G.Q. Zhang, and J.E. Samuel. Both iNOS and NADPH oxidase contribute to the control of virulent phase I Coxiella burnetii infections. 2004. Infect. Immun. 72:6666-6675.
Zamboni, D.A, M. A. Campos, A, C. T. Torrecilhas, K. Kiss, J. E. Samuel, D. T. Golenbock, F. N. Lauw, C. R. Roy, I. C. Almeida,and R. T. Gazzinelli. Stimulation of Toll-like Receptor 2 by Coxiella burnetii Is Required for Macrophage Production of Pro-inflammatory Cytokines and Resistance to Infection. 2004. J. Biol. Chem. 279:54405-54415.
Brennan, R.E., and J.E. Samuel. Evaluation of Coxiella burnetii antibiotic susceptibilities by real-time PCR assay. J. Clin. Microbiol. 2003. 41:1553-1562.
Matise, I., N. A. Cornick, J.E. Samuel, H.W. Moon. Binding of Shiga toxin 2E to porcine erythrocytes in vivo and in vitro. Infect. Immun. 2003. 71:5194-5201.
Seshadri, I.T. Paulsen, J.A. Eisen, T.D. Read, K.E. Nelson, N. Ward, W.C. Nelson, H. Tettelin, T. M. Davidsen, M. J. Beanan, R.T. Deboy, S.C. Daugherty, L.M. Brinkac, R. Madupu, R.J. Dodson, K.H. Lee, H.A. Carty, D. Scanlan, H.A. Thompson, R.A. Heinzen, J.E. Samuel, C.M. Fraser, and J.F. Heidelberg. Complete genome sequence of the Q-fever pathogen, Coxiella burnetii. Proc. Nat. Acad. Sci. USA 2003. 100:5455-5460.
Varghees, S.V., K. Kiss, and J.E. Samuel. Cloning and characterization of the major outer membrane protein from Coxiella burnetii. Infect. Immun. 2002. 70:6741-6750R.