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All natural  Leishmania  infections start in the skin; however, little is known of the contribution made by the sand fly vector to the earliest events in mammalian infection, especially in inflamed skin that can rapidly kill invading parasites. During transmission sand flies regurgitate a proteophosphoglycan gel synthesized by the parasites inside the fly midgut, termed promastigote secretory gel (PSG). Regurgitated PSG can exacerbate cutaneous leishmaniasis. Here, we show that the amount of  Leishmania mexicana  PSG regurgitated by  Lutzomyia longipalpis  sand flies is proportional to the size of its original midgut infection and the number of parasites transmitted. Furthermore, PSG could exacerbate cutaneous  L. mexicana  infection for a wide range of doses (10–10,000 parasites) and enhance infection by as early as 48 hours in inflamed dermal air pouches. This early exacerbation was attributed to two fundamental properties of PSG: Firstly, PSG powerfully recruited macrophages to the dermal site of infection within 24 hours. Secondly, PSG enhanced alternative activation and arginase activity of host macrophages, thereby increasing L-arginine catabolism and the synthesis of polyamines essential for intracellular parasite growth. The increase in arginase activity promoted the intracellular growth of  L. mexicana  within classically activated macrophages, and inhibition of macrophage arginase completely ablated the early exacerbatory properties of PSG  in vitro  and  in vivo . Thus, PSG is an essential component of the infectious sand fly bite for the early establishment of  Leishmania  in skin, which should be considered when designing and screening therapies against leishmaniasis.

Proteophosophoglycans Regurgitated by Leishmania-Infected Sand Flies Target the L-Arginine Metabolism of Host Macrophages to Promote Parasite Survival