PHLEBOTOMUS-PAPATASI SALIVA INHIBITS PROTEIN PHOSPHATASE-ACTIVITY ANDNITRIC-OXIDE PRODUCTION BY MURINE MACROPHAGES

Leishmania parasites, transmitted by phlebotomine sand flies, are obli gate intracellular parasites of macrophages, The sand fly Phlebotomus papatasi is the vector of Leishmania major, a causative agent of cutan eous leishmaniasis in the Old World, and its saliva exacerbates parasi te proliferation and lesion growth in experimental cutaneous leishmani asis, Here we show that P. papatasi saliva contains a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A of murine macroph ages. We further demonstrate that P. papatasi saliva down regulates ex pression of the inducible nitric oxide synthase gene and reduces nitri c oxide production in murine macrophages. Partial biochemical characte rization of the protein phosphatase and nitric oxide inhibitor indicat ed that it is a small, ethanol-soluble molecule resistant to boiling, proteolysis, and DNase and RNase treatments, We suggest that the P. pa patasi salivary protein phosphatase inhibitor interferes with the abil ity of activated macrophages to transmit signals to the nucleus, there by preventing up regulation of the induced nitric oxide synthase gene and inhibiting the production of nitric oxide, Since nitric oxide is t oxic to intracellular parasites, the salivary protein phosphatase inhi bitor may be the mechanism by which P. papatasi saliva exacerbates cut aneous leishmaniasis.