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Infection and Immunity, April 2004, p. 1920-1928, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.1920-1928.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major

Pascale Kropf,1,{dagger} Marina A. Freudenberg,2,{dagger} Manuel Modolell,2,{dagger} Helen P. Price,3,{dagger} Shanti Herath,1 Simone Antoniazi,1 Chris Galanos,2 Deborah F. Smith,3 and Ingrid Müller1*

Faculty of Medicine, Department of Immunology,1 Faculty of Life Sciences, Wellcome Trust Laboratories for Molecular Parasitology and Centre for Molecular Microbiology and Infection, Department of Biological Sciences, Imperial College London, London, United Kingdom,3 Max-Planck-Institut für Immunbiologie, Freiburg, Germany2

Received 14 August 2003/ Returned for modification 6 October 2003/ Accepted 7 January 2004

The essential role of Toll-like receptors (TLR) in innate immune responses to bacterial pathogens is increasingly recognized, but very little is known about the role of TLRs in host defense against infections with eukaryotic pathogens. For the present study, we investigated whether TLRs contribute to the innate and acquired immune response to infection with the intracellular protozoan parasite Leishmania major. Our results show that TLR4 contributes to the control of parasite growth in both phases of the immune response. We also addressed the mechanism that results in killing or growth of the intracellular parasites. Control of parasite replication correlates with the early induction of inducible nitric oxide synthase in TLR4-competent mice, whereas increased parasite survival in host cells from TLR4-deficient mice correlates with a higher activity of arginase, an enzyme known to promote parasite growth. This is the first study showing that TLR4 contributes to the effective control of Leishmania infection in vivo.

* Corresponding author. Mailing address: Faculty of Medicine, Department of Immunology, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44-020 7594 3732. Fax: 44-20 7402 0653. E-mail: i.muller{at}ic.ac.uk.

Editor: S. H. E. Kaufmann

{dagger} P.K., M.A.F., M.M., and H.P.P. contributed equally to this work.

Infection and Immunity, April 2004, p. 1920-1928, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.1920-1928.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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