David Sacks, Ph.D.
Chief, Intracellular Parasite Biology Section
Description of Research Program
Our research focuses on the immunology and cell biology of leishmanial infections and the biology of Leishmania parasites within their mammalian hosts and sand-fly vectors. The ultimate goal of this work is to develop new strategies for treatment and prevention of leishmanial infections based on our research insights. These insights also may have relevance to diseases, such as tuberculosis, caused by other intracellular pathogens, or to other vector-borne diseases, such as malaria.
Experimental mouse infection models that reproduce natural sand-fly challenge are being used to define the mechanisms of acquired resistance and the immunoregulatory mechanisms controlling persistent infection following clinical cure, which is a hallmark of leishmanial infection in human hosts. CD8+ T cells were found to be an essential component of acquired resistance, and the cell biology of Class I processing of exogenous parasite antigens, termed cross-presentation, is being analyzed using transgenic parasites expressing ovalbumin. IL-10 produced by CD4+CD25+ regulatory T cells has been found to control persistent infections, and the specificity, homing properties, and regulatory targets are being studied in detail.
Understanding molecular interactions at the sand fly-Leishmania interface is fundamental to any study of vector competence and disease transmission. We are studying Leishmania-sand fly interactions in the context of the potential barriers to complete development that exist within the midgut of phlebotomine flies, and the parasite-derived molecules that have evolved to overcome these barriers and permit the development of transmissible infections to proceed.
Great emphasis has been placed on developing the first reproducible model of leishmaniasis transmitted by sand-fly bite. The primary goal of these studies has been to define the role of vector saliva in modulating the host response to sand- fly-transmitted parasites. These studies have led to a novel approach to vaccination against Leishmania infection using recombinant proteins or DNA vaccines encoding saliva antigens.
Selected Recent Publications
To view a complete listing, visit PubMed.
Houde M, Bertholet S, Gagnon E, Brunet S, Goyette G, Laplante A, Thibault P, Sacks D and Desjardins M. ER-mediated phagocytosis: phagosomes are competent organelles for antigen cross presentation. Nature 425: 402-406, 2003.
Belkaid Y, Piccirillo CA, Mendez A, Shevach EM, Sacks D. CD4+CD25+ immunoregulatory T lymphocytes control Leishmania major persistence and immunity. Nature 420:502-507, 2002.
Belkaid Y, Hoffmann K, Mendez S, Kamhawi S, Udey M, Wynn T, and Sacks, D. The role of IL-10 in the persistence of Leishmania major in the skin following healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194:1497-1506, 2001.
Mendez S, Gurunathan S, Kamhawi S, Belkaid Y, Moga M, Skeiky Y, Campos-Neto A, Reed S, Seder R, and Sacks D. The potency and durability of DNA- and protein-based vaccines against Leishmania major evaluated using low dose, intra-dermal challenge. J. Immunol. 166:5122-5128, 2001.
Kamhawi, S., Belkaid, Y., Modi, G., Rowton, E., and Sacks, D. Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290:1351, 2000.
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