Phlebotomus papatasi saliva inhibits protein phosphatase activity and nitric oxide production by murine macrophages.

Department of Parasitology, The Kuvin Center for the Study of Infectious and Tropical Diseases, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Infection and Immunity (Impact Factor: 4.16). 04/1998; 66(4):1534-7.
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leishmania parasites are inoculated into host skin together with sand fly saliva and multiple exposures to uninfected sand fly bites protect mice against Leishmania infection. However, sand fly vectors differ in composition of the saliva and therefore the protection elicited by their salivary proteins was shown to be species-specific. On the other hand, the optimal vaccine based on sand fly salivary proteins should be based on conserved salivary proteins conferring cross-reactivity. In the present study we therefore focused on cross-protective properties of saliva from Phlebotomus papatasi and Phlebotomus duboscqi, the two natural vectors of Leishmania major. Two groups of mice exposed to bites of P. papatasi and two control, non-immunized groups were infected with L. major promastigotes along with either P. papatasi or P. duboscqi salivary gland homogenate. All mice were followed for the development of Leishmania lesions, parasite burdens, specific antibodies, and for production of NO, urea, or cytokines by peritoneal macrophages. Protection against Leishmania infection was observed not only in exposed mice challenged with homologous saliva but also in the group challenged with P. duboscqi saliva. Comparing both exposed groups, no significant differences were observed in parasite load, macrophage activity, or in the levels of anti-L. major and anti-P. papatasi/P. duboscqi antibodies. This is the first study showing cross-protection caused by salivary antigens of two Phlebotomus species. The cross-protective effect suggests that the anti-Leishmania vaccine based on P. papatasi salivary proteins might be applicable also in areas where L. major is transmitted by P. duboscqi. Copyright © 2015. Published by Elsevier B.V.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leishmaniases are worldwide diseases transmitted to the vertebrate host by the bite of an infected sand-fly. Sand-fly biting and parasite inoculation are accompanied by the injection of salivary molecules, whose immunomodulatory properties are actively being studied. This mini review focuses on how the interactions between sand-fly saliva and the immune system may shape the outcome of infection, given its immunomodulatory properties, in experimental models and in the endemic area. Additionally, we approach the recent contributions regarding the identification of individual salivary components and how these are currently being considered as additional components of a vaccine against leishmaniasis.
    Frontiers in Immunology 11/2013; 4:375. DOI:10.3389/fimmu.2013.00375
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: World health organization highlighted the requirement for development of new drugs for filariasis. In the present study antifilarial screening was carried out against Setaria cervi adult filarial with varying concentrations of Tetracycline, Rifampicin and Doxycycline (2 -20 mg/ml) individually to find out any involvement of oxidative mechanism in the anti-filarial effect of these antibiotics in vitro. Reduction in motility of the adult was measured after 24h in terms of MTT reduction assay and correlated with the levels of MDA and nitric oxide. Significant reduction in motility was recorded with increasing concentration of Tetracycline and Rifampicin but with Doxycycline the effect was not marked. Antibiotics with high antifilarial activity revealed significant association with oxidative stress parameters in a dose dependent manner. The results suggest that oxidative stress might be exploited to design and development of novel antifilarial drug candidate.
    Journal of Pharmacy and Pharmaceutical Sciences 11/2013; 3(1):583-591. · 1.68 Impact Factor


Available from
May 17, 2014