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Infect Immun, April 1998, p. 1534-1537, Vol. 66, No. 4
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Phlebotomus papatasi Saliva Inhibits Protein Phosphatase Activity and Nitric Oxide Production by Murine Macrophages

John Waitumbi and Alon Warburg^*

Department of Parasitology, The Kuvin Center for the Study of Infectious and Tropical Diseases, Hebrew University-Hadassah Medical School, Jerusalem, Israel

Received 20 October 1997/Returned for modification 25 November 1997/Accepted 8 January 1998

Leishmania parasites, transmitted by phlebotomine sand flies, are obligate intracellular parasites of macrophages. The sand fly Phlebotomus papatasi is the vector of Leishmania major, a causative agent of cutaneous leishmaniasis in the Old World, and its saliva exacerbates parasite proliferation and lesion growth in experimental cutaneous leishmaniasis. Here we show that P. papatasi saliva contains a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A of murine macrophages. We further demonstrate that P. papatasi saliva down regulates expression of the inducible nitric oxide synthase gene and reduces nitric oxide production in murine macrophages. Partial biochemical characterization of the protein phosphatase and nitric oxide inhibitor indicated that it is a small, ethanol-soluble molecule resistant to boiling, proteolysis, and DNase and RNase treatments. We suggest that the P. papatasi salivary protein phosphatase inhibitor interferes with the ability of activated macrophages to transmit signals to the nucleus, thereby preventing up regulation of the induced nitric oxide synthase gene and inhibiting the production of nitric oxide. Since nitric oxide is toxic to intracellular parasites, the salivary protein phosphatase inhibitor may be the mechanism by which P. papatasi saliva exacerbates cutaneous leishmaniasis.

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^* Corresponding author. Mailing address: Department of Parasitology, Hebrew University-Hadassah Medical School, P.O. Box 12272, Ein Kerem, Jerusalem 91120, Israel. Phone: 972-2-6757080. Fax: 972-2-6757425. E-mail: Warburg{at}cc.huji.ac.il.

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