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Office: (859) 323-8701
Fax: (859) 257-8994
Lab: (859) 323-8702
Email: sdora2@uky.edu
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Sarah E.F. D'Orazio, Ph.D.
Assistant Professor
Doctoral Studies: University of Miami.
Postdoctoral: Harvard Medical School.
Research Statement:
Research in my lab is focused on understanding how infection with intracellular bacterial pathogens such as Listeria monocytogenes (Lm) can effectively be cleared by the host. We use a variety of bacteriological and immunological approaches to study the complex interplay between the virulence strategies of the pathogen and the immune responses of the host.
Lm are Gram-positive bacteria that cause food borne illness, usually through the ingestion of unpasteurized cheeses or “ready-to-eat” foods such as deli meats. Lm is widespread in nature and is resistant to most of the techniques used to protect our food supply, such as salting, drying, and refrigeration. Systemic spread of Lm can result in serious outcomes, particularly for pregnant women and neonates, including meningoencephalitis and spontaneous abortion. Although systemic listeriosis is not common, the high fatality rate for these infections (25-30% of hospital cases) make it a significant public health concern.
Current projects in the lab include:
1) Role of LLO in triggering a rapid IFNg response. Infection with Lm triggers a robust, rapid IFNg response in some, but not all, individuals, and we showed that rapid IFNg-responder mice are significantly more resistant to Lm infection than non-responder mice. Multiple mechanisms appear to contribute to this uniquely robust innate immune response, and at least two of these pathways are dependent on secretion of the pore-forming bacterial toxin listeriolysin O. Current work is focused on dissecting both the direct and indirect mechanisms mediated by LLO that lead to rapid IFNg secretion during Lm infection.
2) Lm-specific T cells recognize antigens presented by novel MHC-I proteins. CD8+ T cells are alerted to the presence of intracellular bacteria via specific recognition of bacterial antigens displayed on the infected cell surface by MHC-I molecules. In the mouse, there are 3 well-characterized MHC molecules (K, D, and L, now collectively known as MHC-Ia) and several other “non-classical” or MHC-Ib molecules that are less well understood. Using a MHC-Ia deficient mouse model, we showed that MHC-Ib restricted CD8+ T cells alone were sufficient to protect mice against challenge with Lm. Current work in the lab is focused on identifying the relevant MHC-Ib proteins capable of presenting antigen to T cells during Lm infection. Since MHC-Ib proteins generally display little or no polymorphism, antigens that bind to MHC-Ib may be very useful for inclusion in vaccines that could effectively protect all human (regardless of MHC haplotype) against infection with intracellular pathogens such as Lm.
Selected Recent Publications:
Bou Ghanem, E.N., Denise S. McElroy, and Sarah E.F. D’Orazio. (2009) Multiple mechanisms of cytokine induction are involved in triggering the rapid IFNg response by CD8+ T cells during Listeria monocytogenes infection. Infect. Immun. 77 (4): 1492-1501. [Abstract]
McElroy, Denise S., Taylor J. Ashley, and Sarah E.F. D’Orazio. (2009) Lymphocytes serve as a reservoir for Listeria monocytogenes growth during infection of mice. Microbial Pathogenesis. 46 (4): 214-221. [Abstract]
McElroy, Denise, S., Adina M. Badstibner, and Sarah E.F. D’Orazio. (2007) Use of the CD107 mobilization assay reveals that cytotoxic T lymphocytes with a novel MHC-Ib restriction are activated during Listeria monocytogenes infection. J. Immunol. Methods. 328: 45-52. [Abstract]
D’Orazio, Sarah E.F., Matthew J. Troese, and Michael N. Starnbach. (2006) Cytosolic localization of Listeria monocytogenes triggers an early IFNg response by CD8+ T cells that correlates with innate resistance to infection. J. Immunol. 177 (10): 7146-7154. [Abstract]
D'Orazio, S.E.F., C. A. Shaw, and M. N. Starnbach. (2006) H2-M3-restricted CD8+ T cells are not required for MHC class Ib-restricted immunity against Listeria monocytogenes. J. Exp. Med. 203 (2):383-391. [Abstract]
D’Orazio, S.E.F., D. S. Gould, H. L. Ploegh, and M. N. Starnbach. (2003) Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeria monocytogenes infection. J. Immunol. 171: 291-298. [Abstract]
D’Orazio, S. E.F., M. Velasquez, N. R. Roan, O. Naveiras-Torres, and M. N. Starnbach. (2003) The Listeria monocytogenes lemA gene product is not required for intracellular infection or to activate fMIGWII-specific-T cells. Infect. Immun. 71 (12): 6721-6727. [Abstract]
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