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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 the factors that determine host susceptibility or resistance to infection with the intracellular bacterial pathogen Listeria monocytogenes. We use a variety of bacteriologic and immunologic approaches to study the complex interplay between the virulence strategies of the pathogen and the protective immune responses of the host.
L. monocytogenes are Gram-positive bacteria that cause food borne illness after ingestion of “ready-to-eat” foods such as deli meats, unpasteurized cheeses or processed produce. The high fatality rate (~30%) for systemic listeriosis makes it a significant public health concern for high-risk groups including neonates, pregnant women, and people in other categories (the elderly, transplant recipients, other immune comprised people with chronic diseases) that are steadily increasing in number due to medical advances.
We recently developed a novel mouse model for oral transmission of L. monocytogenes that closely mimics all phases of human disease: (1) ingestion of contaminated food, (2) a distinct gastrointestinal phase followed by (3) varying degrees of systemic spread in susceptible vs. resistant mouse strains, and (4) late stage spread to the brain. We are currently using this model to understand how L. monocytogenes colonize the colon and then disseminate to peripheral tissues. This project is funded by NIAID.
Another focus of the lab in recent years has been to define the role of CD8+ T cells in innate immune defense against infection. Using both murine and human systems, we have shown that a subset of CD8+ T cells in some, but not all individuals, can be induced to rapidly secrete interferon-gamma within 6-10 hours after L. monocytogenes infection. This is a cytokine driven process that does not involve signaling through the antigen-specific T cell receptor. We hypothesize that “bystander” activation of CD8+ T cells in resistant individuals facilitates the activation of interferon-gamma dependent clearance mechanisms that rapidly reduce bacterial burden. In susceptible individuals, interferon-gamma secretion by CD8+ T cells is delayed or deficient, allowing L. monocytogenes to replicate exponentially. Current projects in the lab include: 1) identifying the particular T cell subsets that rapidly secrete interferon-gamma after ingestion of contaminated food and 2) defining the interferon-gamma dependent mechanisms that promote clearance of L. monocytogenes in vivo.
Recent Publications:
Bou Ghanem, E.N., G.S. Jones, T. Myers-Morales, P.D. Patil, A.N. Hidayatullah, and S.E.F. D'Orazio. (2012) InlA promotes dissemination of Listeria monocytoegnes to the mesenteric lymph nodes during food borne infection of mice. PLoS Pathogens. 8(11):e1003015.
[http://www.ncbi.nlm.nih.gov/pubmed/23166492]
Bou Ghanem, EN and S.E.F. D'Orazio. (2011) Human CD8+ T cells display a differential ability to undergo cytokine-driven bystander activation. Cell. Immunol. 272(1):79-86.
[http://www.ncbi.nlm.nih.gov/pubmed/21978649]
Bou Ghanem, E.N., Christina C. Nelson and Sarah E.F. D’Orazio. (2011) T cell intrinsic factors contribute to the differential ability of CD8+ T cells to rapidly secrete IFNg in the absence of antigen. J. Immunol. 186(3):1703-12 [Abstract]
Murapa, Patience, Martin R. Ward, Siva K. Ghandhapudi, Jerold G. Woodward and Sarah E.F. D’Orazio. (2011) HSF-1 protects mice from rapid death during Listeria monocytogenes infection by regulating production of TNFa during fever. Infect. Immun. 79(1): 177-184. [Abstract]
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]
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