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Infection and Immunity, January 2004, p. 176-186, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.176-186.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of Toll-Like Receptor 4 in Induction of Cell-Mediated Immunity and Resistance to Brucella abortus Infection in Mice

Marco A. Campos,1,2 Gracia M. S. Rosinha,1,3 Igor C. Almeida,4 Xirlene S. Salgueiro,4 Bruce W. Jarvis,5 Gary A. Splitter,5 Nilofer Qureshi,6 Oscar Bruna-Romero,2 Ricardo T. Gazzinelli,1,2 and Sergio C. Oliveira1*

Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais,1 Centro de Pesquisas René Rachou, Oswaldo Cruz Foundation, Belo Horizonte,2 EMBRAPA-CNPC, Sobral-CE,3 Department of Parasitology, University of São Paulo, São Paulo, Brazil,4 Department of Animal Health & Biomedical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706,5 Department of Basic Medical Science, Medical School, University of Missouri, Kansas City, Missouri 641086

Received 31 July 2003/ Returned for modification 20 September 2003/ Accepted 3 October 2003

Initial host defense to bacterial infection is executed by innate immunity, and therefore the main goal of this study was to examine the contribution of Toll-like receptors (TLRs) during Brucella abortus infection. CHO reporter cell lines transfected with CD14 and TLRs showed that B. abortus triggers both TLR2 and TLR4. In contrast, lipopolysaccharide (LPS) and lipid A derived from Brucella rough (R) and smooth (S) strains activate CHO cells only through TLR4. Consistently, macrophages from C3H/HePas mice exposed to R and S strains and their LPS produced higher levels of tumor necrosis factor alpha (TNF-{alpha}) and interleukin-12 compared to C3H/HeJ, a TLR4 mutant mouse. The essential role of TLR4 for induction of proinflammatory cytokines was confirmed with diphosphoryl lipid A from Rhodobacter sphaeroides. Furthermore, to determine the contribution of TLR2 and TLR4 in bacterial clearance, numbers of Brucella were monitored in the spleen of C3H/HeJ, C3H/HePas, TLR2 knockout, and wild-type mice at 1, 3, and 6 weeks following B. abortus infection. Interestingly, murine brucellosis was markedly exacerbated at weeks 3 and 6 after infection in animals that lacked functional TLR4 (C3H/HeJ) compared to C3H/HePas that paralleled the reduced gamma interferon production by this mouse strain. Finally, by mass spectrometry analysis we found dramatic differences on the lipid A profiles of R and S strains. In fact, S lipid A was shown to be more active to trigger TLR4 than R lipid A in CHO cells and more effective in inducing dendritic cell maturation. In conclusion, these results indicate that TLR4 plays a role in resistance to B. abortus infection and that S lipid A has potent adjuvant activity.

* Corresponding author. Mailing address: Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, MG, Brazil, 30161-970. Phone and fax: 55-31-34992666. E-mail: scozeus{at}icb.ufmg.br.

Editor: J. T. Barbieri

Infection and Immunity, January 2004, p. 176-186, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.176-186.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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