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.
Highlights
Leishmaniasis comprises human and animal diseases caused by parasites of the genus Leishmania that are transmitted by the bite of infected sand flies [1]
The killing mechanism(s) of pathogens trapped by neutrophil extracellular traps (NETs) is poorly understood, the relevance of secreted endonuclease as a mechanism of evading the microorganism-killing activity of NETs has been highlighted by the presence of endonuclease activity in bacteria-evading, NET-dependent killing [17,22]
The mechanism by which Leishmania promastigotes evade killing by neutrophils may be related to their ability to block oxidative burst and to enter a nonlytic compartment unable to fuse with lysosomes [23] or by resisting the microbicidal activity of NETs [11]
Summary
Leishmaniasis comprises human and animal diseases caused by parasites of the genus Leishmania that are transmitted by the bite of infected sand flies [1]. Leishmania transmission occurs when an infected sand fly probes the host’s skin in search of a blood meal. Sand flies salivate into the host’s skin. Saliva contains powerful pharmacologic components that mediate blood-feeding success and facilitate Leishmania infection, first shown when Lutzomyia longipalpis salivary glands (SGs) were reported to enhance Leishmania major infection in mice [2,3]. The powerful Lu. longipalpis vasodilator maxadilan along with hyaluronidase were shown to facilitate transmission and establishment of L. major parasites [5,6]; as we show here, these salivary compounds are not the only active components of sand fly saliva that exacerbate parasite infection
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