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J. Biol. Chem., Vol. 279, Issue 52, 54405-54415, December 24, 2004

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Stimulation of Toll-like Receptor 2 by Coxiella burnetii Is Required for Macrophage Production of Pro-inflammatory Cytokines and Resistance to Infection^*

From the ^aSection of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, ^cCentro de Pesquisas René Rachou, Oswaldo Cruz Foundation, Belo Horizonte MG 30190-002, the ^dDepartment of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil, the ^fDepartment of Medical Microbiology and Immunology, Texas A & M University System, College Station, Texas 77843, ^gDivision of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ^jDepartment of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte MG 31270-901, Brazil

Innate and adaptive immune responses are initiated upon recognition of microbial molecules by Toll-like receptors (TLRs). We have investigated the importance of these receptors in the induction of pro-inflammatory cytokines and macrophage resistance to infection with Coxiella burnetii, an obligate intracellular bacterium and the etiological agent of Q fever. By using a Chinese hamster ovary/CD14 cell line expressing either functional TLR2 or TLR4, we determined that C. burnetii phase II activates TLR2 but not TLR4. Macrophages deficient for TLR2, but not TLR4, produced less tumor necrosis factor- and interleukin-12 upon C. burnetii infection. Furthermore, it was found that TLR2 activation interfered with C. burnetii intracellular replication, as macrophages from TLR2-deficient mice were highly permissive for C. burnetii growth compared with macrophages from wild type mice or TLR4-deficient mice. Although LPS modifications distinguish virulent C. burnetii phase I bacteria from avirulent phase II organisms, electrospray ionization-mass spectrometry analysis showed that the lipid A moieties isolated from these two phase variants are identical. Purified lipid A derived from either phase I or phase II LPS failed to activate TLR2 and TLR4. Indeed, the lipid A molecules were able to interfere with TLR4 signaling in response to purified Escherichia coli LPS. These studies indicate that TLR2 is an important host determinant that mediates recognition of C. burnetii and a response that limits growth of this intracellular pathogen.

Received for publication, September 9, 2004 , and in revised form, October 12, 2004.

^* This work was supported in part by CNPq, FAPEMIG (EDT 24000), PRONEX (EDT 2400), FIOCRUZ, United States Public Health Service Grants AI37744, AI448191 (to J. E. S.), AI49309, GM54060 (to D. T. G.), and AI48770 (to C. R. R.) from the National Institutes of Health, and FAPESP Grants 96/9850-0 to Michel Rabinovitch, and FAPESP Grant 98/10495-5 (to I. C. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^e Recipient of a doctoral fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil).

^h Postdoctoral fellow from Netherlands Organization for Scientific Research.

ⁱ Research Fellow from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil).

^k Present address: Dept. of Biological Sciences, Rm. 402, University of Texas, El Paso, TX 79968-0519.

^b Postdoctoral fellow from PEW Latin American Fellows Program. To whom correspondence should be addressed: Yale University School of Medicine, Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Rm. 354, 295 Congress Ave., New Haven, CT 06536. Tel.: 203-737-2409; Fax: 203-737-2630; E-mail: dario.zamboni{at}yale.edu.

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