Alteration of skin immune environment by sand fly saliva across progressive Leishmaniasis

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Summary Visceral leishmaniasis (VL), caused by Leishmania donovani complex spp. causes between 20,000- 40,000 deaths a year. L. infantum is the cause of VL in the Mediterranean basin and imported to both South and North America. L. infantum is zoonotic with canid reservoirs. Leishmania spp. are transmitted primarily between mammalian hosts by female Lutzomyia or Phlebotomus sand flies. It has been established that both sand fly and host factors modulate local dermal immunity when and where parasites first encounter skin, guiding immunity locally and systemically and impacting infection outcomes. Relatively little is known about the skin immune environment during progressive VL, how dermal immune changes alter host infectiousness or responses to immunomodulatory sand fly salivary components. Skin parasite burden in dogs with L. infantum infection correlates with transmission efficiency, more so than parasitemia, though dogs with late-stage disease were less infectious than those with mild-moderate disease. We have shown that asymptomatic VL clinical status was associated in dogs, as in humans, with productive Th1 type responses, while symptomatic infection correlated with presence of exhausted CD4+ and CD8+ T cells, significant expression of Programmed Death 1 (PD-1) and its ligand, PD-L1 on both B cells and macrophages and loss of macrophage parasite clearance. These findings collectively lead us to hypothesize that immune cell responses in subclinical or clinically infected hosts’ skin, whether from dogs or humans, dictate host infectiousness. We will address this hypothesis through three specific aims in this proposed work, 1) Identify unique dermal immune environments in subclinical vs. clinical hosts that alter infectiousness to naïve sand flies, 2) Evaluate how the functions of sand fly salivary proteins are impacted by skin changes during progressive VL leading to new understanding of vector saliva-host interactions and how they contribute to infectiousness to sand flies and 3) Evaluate how alteration of the dermal immune environment through dermal immunotherapy alters bite-site inflammation and transmission. The work proposed here is therefore significant, as it provides infection control relevant evidence regarding the dermal microenvironment and how it alters infectivity during progressive L infantum infection. The studies proposed here are significantly innovative as they quantitatively on a spatial level assess how parasite burden and different dermal inflammatory states alter infectiousness to sand flies. Using purified salivary antigens, skin biopsy, histopathologic and transcriptome analysis and a key unique natural infection cohort, we will determine how progressive VL alters the landscape in which vector salivary proteins operate with consequences for understanding both host infectiousness and the epidemiology of VL. When completed, findings from these proposed studies will both underscore how progressive dermal inflammation impacts reservoir host infectiousness and provide critical data to further assess appropriate interventions to prevent canine-sand fly-human transmission.