title: Lundep, a sand fly salivary endonuclease increases Leishmania parasite survival in neutrophils and inhibits XIIa contact activation in human plasma.
abstract: Neutrophils are the host's first line of defense against infections, and their extracellular traps (NET) were recently shown to kill Leishmania parasites. Here we report a NET-destroying molecule (Lundep) from the salivary glands of Lutzomyia longipalpis. Previous analysis of the sialotranscriptome of Lu. longipalpis showed the potential presence of an endonuclease. Indeed, not only was the cloned cDNA (Lundep) shown to encode a highly active ss- and dsDNAse, but also the same activity was demonstrated to be secreted by salivary glands of female Lu. longipalpis. Lundep hydrolyzes both ss- and dsDNA with little sequence specificity with a calculated DNase activity of 300000 Kunitz units per mg of protein. Disruption of PMA (phorbol 12 myristate 13 acetate)- or parasite-induced NETs by treatment with recombinant Lundep or salivary gland homogenates increases parasite survival in neutrophils. Furthermore, co-injection of recombinant Lundep with metacyclic promastigotes significantly exacerbates Leishmania infection in mice when compared with PBS alone or inactive (mutagenized) Lundep. We hypothesize that Lundep helps the parasite to establish an infection by allowing it to escape from the leishmanicidal activity of NETs early after inoculation. Lundep may also assist blood meal intake by lowering the local viscosity caused by the release of host DNA and as an anticoagulant by inhibiting the intrinsic pathway of coagulation.
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Andrezza C
authors: AC
authors: Chagas
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Fabiano
authors: F
authors: Oliveira
authors: Laboratory of Emerging Pathogens, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, United States of America.
authors: Alain
authors: A
authors: Debrabant
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Jesus G
authors: JG
authors: Valenzuela
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: José M C
authors: JM
authors: Ribeiro
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Eric
authors: E
authors: Calvo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D015153:Blotting, Western; D004199:Disease Vectors; D004720:Endonucleases / Q000276:immunology / Q000378:metabolism*; D015956:Factor XIIa / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D007891:Leishmania; D007896:Leishmaniasis / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000469:parasitology; D016133:Polymerase Chain Reaction; D011576:Psychodidae / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology*; D012469:Salivary Glands / Q000201:enzymology / Q000276:immunology
chemical_list: D004720:Endonucleases; D015956:Factor XIIa