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Originally published in Science Express on 28 April 2005
Science 10 June 2005:
Vol. 308. no. 5728, pp. 1626 - 1629
DOI: 10.1126/science.1109893
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Reports

TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein

Felix Yarovinsky,1* Dekai Zhang,3 John F. Andersen,2 Gerard L. Bannenberg,4{dagger} Charles N. Serhan,4 Matthew S. Hayden,3 Sara Hieny,1 Fayyaz S. Sutterwala,3 Richard A. Flavell,3 Sankar Ghosh,3 Alan Sher1*

Mammalian Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs). Although TLRs are clearly involved in the detection of bacteria and viruses, relatively little is known about their function in the innate response to eukaryotic microorganisms. Here we identify a profilin-like molecule from the protozoan parasite Toxoplasma gondii that generates a potent interleukin-12 (IL-12) response in murine DCs that is dependent on myeloid differentiation factor 88. T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced IL-12 production and optimal resistance to infection, thereby establishing a role for the receptor in host recognition of protozoan pathogens.

1 Immunobiology Section, Laboratory of Parasitic Diseases; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
2 Medical Entomology Section, Laboratory of Malaria and Vector Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
3 Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

{dagger} Present address: Departamento Genética Molecular de Plantas, Centro Nacional de Biotecnología, 28049 Madrid, Spain.

* To whom correspondence should be addressed. E-mail: asher{at}niaid.nih.gov (A.S.); fyarovinsky{at}niaid.nih.gov (F.Y.)

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   Abstract »    Full Text »    PDF »
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