Neuroendocrine regulation of Phlebotomus perniciosus immunity and microbiota: fighting Leishmania infection

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Vector-borne diseases create considerable risks to human health. Leishmaniases are a group of neglected vector-borne diseases caused by protists parasites from the Leishmania genus. Approximately 350 million people around the world are at risk of being infected with Leishmania, and clinical manifestations in humans vary from cutaneous to visceral types. Leishmania is transmitted to humans by hematophagous female sand flies (Diptera, Psychodidae, Phlebotominae). Here we focus on Phlebotomus perniciosus, the natural vector of Leishmania infantum (the causative agent of visceral leishmaniasis) in the western region of the Mediterranean basin Europe. Leishmania cycle occurs in the sand fly midgut, where parasites must overcome natural barriers such as high activity levels of midgut digestive proteases, the competition with the native gut microbiota, and the activation of sand fly immune responses. Recently it was shown that insect immunity is under hormonal regulation; ecdysone hormone binds to its receptor (EcR) and triggers the expression of IMD immune signalling pathway-related genes. In sand flies gut, the IMD pathway controls Leishmania infection, but ecdysone's role in sand fly immunity and microbiota has never been studied. The NEPHIMLEI project, in a pioneering way, proposes manipulating P. perniciosus neuroendocrine system to affect sand fly gut immunity and microbiota intending the blockage of L. infantum development in the vector. Sand fly ecdysone function will be impaired by azadirachtin (an ecdysone inhibitor) oral treatment or silencing the EcR gene by RNAi. Also, sand fly immunity will be enhanced by suppressing repressor genes from both ecdysone and IMD pathways (Eip75B and caspar, respectively) using the CRISPR/Cas9 system. The altered ecdysone signalling could change P. perniciosus IMD-related immune responses, affecting microbiota and inducing sand fly resistance against L. infantum.