This impairs the ability of the fly to bloodfeed and modifies the bloodfeeding behaviour of the sand fly, resulting in more transmission attempts (the ‘blocked fly hypothesis’ of Leishmania transmission). In mature infections, the PSG can block the anterior sand fly midgut. This process of metacyclogenesis is accompanied by the accumulation of PSG. In the sand fly midgut Leishmania promastigotes develop into infectious metacyclic promastigotes stages. Despite this, we know little of the early immune events that follow transmission.
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This is in part due to this mode of transmission, which has a significant influence on the virulence of the resulting infection. Along with the parasites, the sand fly injects saliva and a parasite-derived, glycan-rich gel termed promastigote secretory gel (PSG)–both of which have been shown to enhance cutaneous leishmaniasis in mice.
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Infection by sand fly bite is very efficient and difficult to replicate using needles. Leishmania is a genus of protozoan parasites transmitted by the bites of infected phlebotomine sand flies. Our findings open the dual possibility of exploiting PSG, or defined components thereof, as a novel wound healing therapy and provide new targets for anti-leishmanial therapeutic design. IGF1-blockade efficiently reduced the virulence of Leishmania infection from sand fly bite transmission indicating that it is essential to the function of PSG during natural infection. IGF1 was essential to both the wound healing and disease-exacerbating properties of PSG, arising from its ability to alternatively activate macrophages. The presence of PSG significantly accelerated wound closure in vitro and in vivo, and this was directed by the presence of IGF1.
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Following a wound to skin preconditioned with PSG, key transcripts associated with inflammation and cell recruitment were enhanced by 4 hours and those associated with epithelial cell differentiation, proliferation and fibrosis were enhanced in the late phase of wound healing including insulin growth factor-1 (IGF1) and its receptor.
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Here we investigate mouse ear-skin response to PSG and find that a significant proportion of up-regulated transcripts are involved in wound healing. During transmission, promastigote secretory gel (PSG) regurgitated from the blocked sand fly gut promote Leishmania infection and exacerbates disease. Our data demonstrate that through the regurgitation of PSG Leishmania exploit the wound healing response of the host to the vector bite by promoting the action of IGF1 to drive the alternative activation of macrophages.įemale phlebotomine sand flies efficiently transmit Leishmania parasites, yet the underlying mechanisms remain poorly understood. Dermal macrophages recruited to air-pouches on the backs of mice revealed that IGF1 was pivotal to the PSG’s ability to promote macrophage alternative activation and Leishmania infection. Antibody blockade of IGF1 ablated the gel’s ability to promote wound closure in mouse ears and significantly reduced the virulence of Leishmania mexicana infection delivered by an individual sand fly bite. Dermal expression of IGF1 was enhanced following an infected sand fly bite and was acutely responsive to the deposition of PSG but not the inoculation of parasites or sand fly saliva. We found that PSG significantly accelerated wound healing in vitro and in mice which was associated with an early up-regulation of transcripts involved in inflammation (IL-1β, IL-6, IL-10, TNFα) and inflammatory cell recruitment (CCL2, CC元, CCL4, CXCL2), followed 6 days later by enhanced expression of transcripts associated with epithelial cell proliferation, fibroplasia and fibrosis (FGFR2, EGF, EGFR, IGF1). These transcripts were transiently up-regulated during the first 6 hours post-wound and enriched for pathways involved in inflammation, cell proliferation, fibrosis, epithelial cell differentiation and wound remodelling. Here we nanoinjected a sand fly egested dose of PSG into BALB/c mouse skin that lead to the differential expression of 7,907 transcripts.
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The interaction between the wound created by the sand fly bite and PSG is not known. In the sand fly midgut secreted proteophosphoglycans from Leishmania form a biological plug known as the promastigote secretory gel (PSG), which blocks the gut and facilitates the regurgitation of infective parasites. Leishmania parasites are transmitted to vertebrate hosts by female phlebotomine sand flies as they bloodfeed by lacerating the upper capillaries of the dermis with their barbed mouthparts.