My laboratory is focused on the basis of host immunity to microbial pathogens. We are examining immune responses to Toxoplasma gondii and malaria infections as an experimental model of host-pathogen interactions.
The primary function of the innate immune system is the detection of pathogens and the rapid activation of host defense mechanisms. While the repertoire of innate immune receptors is very broad, Toll-like receptors (TLRs) appear to be central elements of the innate immune system because of their direct involvement in the control of T cell responses. We have identified that a Toxoplasma gondii protein, profilin, activates dendritic cells (DC) IL-12 production through TLR11. Profilin is an actin binding protein playing critical roles in governing a number of motility related functions in the parasite. We further established that TLR11 activation of DC is not limited to T. gondii profilin and that this innate receptor serves as a generalized Pattern Recognition Receptor for apicomplexan protozoan parasites such as Toxoplasma gondii, Cryptosporidium spp., Plasmodium spp. These important pathogens provide unique experimental models for studying the role of CD4+ and CD8+ T lymphocytes in acute and chronic infectious diseases.
The research in the lab concerns studies on the functional and structural basis of self/non-self discrimination by DC, on the cell biology of antigen processing and presentation, including intracellular antigen transport, and on consequences of impaired self/non-self discriminations in infectious disease models.
There are currently three main projects in my lab which will address the following questions:
Project#1. What are the molecular and structural mechanisms of translation of innate recognition of pathogens into the induction of an adaptive immune response against non-self antigens?
Project#2. How does the same antigen-presenting cell (APC) provide intrinsically conflicting signals for the initiation of an immune response against non-self antigens and maintain unresponsiveness to self antigens?
Project#3. What are the consequences of impaired self/non-self recognition during the course of microbial infection?
We will address these questions by characterizing the immune response to Toxoplasma gondii and Plasmodium spp. in the absence of TLR-recogntion. We will also use genetically engineered knock-in and knock-out parasite strains to study the function of TLR during host responses to parasitic infection in vivo.
RESEARCH INTERESTS
Infectious diseases
Innate immunity
Toll-like receptors
Dendritic cells
RECENT PUBLICATIONS
F Plattner; F Yarovinsky; S Romero; D Didry; M Carlier; A Sher; D Soldati, "Toxoplasma profilin is essential for host cell invasion and TLR dependent induction of Interleukin-12" Cell Host&Microbe, in press 2008
Yarovinsky F, Kanzler H, Hieny S, Coffman RL, Sher A, "Toll-like receptor recognition regulates immunodominance in an antimicrobial CD4+ T cell response" Immunity, Oct;25(4):655-64., October 2006
Felix Yarovinsky and Alan Sher, "Toll-like receptor recognition of Toxoplasma gondii" Int J Parasitol, Mar;36(3):255-9, March 2006
SIGNIFICANT PUBLICATIONS
Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A, "TLR11 activation of dendritic cells by a protozoan profilin-like protein" Science, 10;308(5728):1626-9, June 2005
Yarovinsky F, Kanzler H, Hieny S, Coffman RL, Sher A., "Toll-like receptor recognition regulates immunodominance in an antimicrobial CD4+ T cell response" Immunity, Oct;25(4):655-64, October 2006
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