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Infection and Immunity, November 2006, p. 6272-6279, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00853-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Host Protein Tyrosine Phosphatase SHP-1 in Leishmania donovani-Induced Inhibition of Nitric Oxide Production

Geneviève Forget,1 David J. Gregory,2 Lorie A. Whitcombe,2,4 and Martin Olivier2,3,4*

Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada,1 Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre,2 Departments of Experimental Medicine,3 Microbiology and Immunology, McGill University, Montréal, Canada4

Received 6 June 2005/ Returned for modification 25 July 2005/ Accepted 25 July 2006

In order to survive within the macrophages of its host organism, the protozoan parasite Leishmania inhibits a number of critical, gamma interferon (IFN-{gamma})-inducible, macrophage functions, including the generation of nitric oxide. We have previously shown that the protein tyrosine phosphatase SHP-1 (Src-homology 2 domain containing phosphatase-1) is activated during Leishmania infection and plays an important role in both the survival of Leishmania within cultured macrophages and disease progression in vivo by inhibiting nitric oxide production. Here we use a SHP-1–/– macrophage cell line derived from motheaten mice to address the mechanisms by which SHP-1 prevents IFN-{gamma}-dependent nitric oxide production during Leishmania donovani infection. We show that Leishmania inhibits nitric oxide production in response to IFN-{gamma} poorly in SHP-1-deficient macrophages. This correlates with the inability of Leishmania to alter JAK2 and mitogen-activated protein kinase extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and to prevent nuclear translocation of transcription factors NF-{kappa}B and AP-1, although the latter two to a lesser extent. Surprisingly, Leishmania inactivated the transcription factor STAT1 to a similar extent in SHP-1-deficient and wild-type macrophages, so STAT1 is not necessary for nitric oxide production by infected macrophages. Overall, this study demonstrates that induction of SHP-1 by Leishmania is vital for inhibition of nitric oxide generation and that this inhibition occurs through the inactivation of JAK2 and ERK1/2, and transcription factors NF-{kappa}B and AP-1.

* Corresponding author. Mailing address: McGill University, Duff Medical Building, Room 610, Department of Microbiology and Immunology, 3775 University Street, Montréal, Qc, H3A 2B4, Canada. Phone: (514) 398-559. Fax: (514) 398-7052. E-mail: martin.olivier{at}mcgill.ca.

Editor: W. A. Petri, Jr.

Infection and Immunity, November 2006, p. 6272-6279, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00853-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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