The primary functions of the innate immune system are the detection of pathogens and the rapid activation of host defense mechanisms. My laboratory is focused on the identification of microbial components that are responsible for initiation of innate immune responses. We are seeking to understand how innate recognition regulates adaptive immune responses to microbial pathogens.
Host-Pathogen interactions
While the repertoire of innate immune receptors is very broad, Toll-like receptors (TLRs) appear to be central elements of the innate immune system due to their direct involvement in the control of T cell responses. Most of our work is focused on TLR-dependent recognition of protozoan parasites. Organisms in this group cause a number of important diseases of global importance including malaria and toxoplasmosis. The research in our lab is concerned with studies on the functional and structural basis of TLR activation by protozoan parasites, the cell biology of dendritic cells, and the consequences of impaired pathogen recognition in infectious disease models. In our work with protozoan parasites, we have identified that a Toxoplasma gondii protein, profilin, activates dendritic cells through TLR11. Profilin is an actin binding protein that plays 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 Cryptosporidium spp. and Plasmodium spp. These important pathogens provide unique experimental models for studying the role of CD4+ and CD8+ T lymphocytes in both acute and chronic infectious diseases.
Mucosal innate immunity
The gastrointestinal tract of mammals is heavily colonized with a complex and dynamic microbial community. Gut microbial communities have a broad impact on many aspects of host physiology, including the immune system. At the same time, the mucosal surfaces represent major sites of entry for numerous infectious agents. Importantly, epithelial cells, as well as bone marrow-derived dendritic cells (DC) and macrophages, play TLR-dependent immunosensory roles in the gut. The relative contributions of these cells to a balanced response to commensal bacteria and intestinal pathogens are not completely understood. Furthermore, it is not clear how DCs and macrophages can discriminate between pathogenic and commensal bacteria, given that both types of microorganisms share multiple common elements responsible for the activation of both innate and adaptive immune responses. Without answers to these important questions, the ability to modulate mucosal immune responses is limited. One of our laboratory’s major interests is to gain a basic understanding of how mucosal TLRs regulate both symbiotic host-microbial relationships and inflammatory reactions in vivo. Our current goal is to identify cell type(s) that are essential for the TLR-mediated effects of gut commensals and to delineate how these cells impact the interaction of commensal bacteria with intestinal tissues.
RESEARCH INTERESTS
Infectious diseases
Innate immunity
Toll-like receptors
Dendritic cells
RECENT PUBLICATIONS
Alicia Benson, Reed Pifer, Cassie L. Behrendt, Lora V. Hooper, Felix Yarovinsky, "Gut commensal bacteria direct a protective immune response against Toxoplasma gondii" Cell Host&Microbe, 2009
Felix Yarovinsky, "Toll-like receptors and their role in host resistance to Toxoplasma gondii" Immunology Letters, doi:10.1016/j.imlet.2008. July 2008
Yarovinsky F, Hieny S, Sher A, "Recognition of Toxoplasma gondii by TLR11 prevents parasite-induced immunopathology" J Immunol, 181(12):8478-84, December 2008
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, 14;3(2):77-87, February 2008
Sanders CJ, Franchi L, Yarovinsky F, Uematsu S, Akira S, Nu?ez G, Gewirtz AT, "Induction of adaptive immunity by flagellin does not require robust activation of innate immunity" Eur J Immunol, 39(2):359-71, February 2009
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
Alicia Benson, Reed Pifer, Cassie L. Behrendt, Lora V. Hooper, Felix Yarovinsky, "Gut commensal bacteria direct a protective immune response against Toxoplasma gondii" Cell Host&Microbe, in press 2009
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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