Abstract
Sand flies bite mammalian hosts to obtain a blood meal, driving changes in the host inflammatory response that support the establishment of Leishmania infection. This effect is partially attributed to components of sand fly saliva, which are able to recruit and activate leukocytes. Our group has shown that heme oxygenase-1 (HO-1) favors Leishmania survival in infected cells by reducing inflammatory responses. Here, we show that exposure to sand fly bites is associated with induction of HO-1 in vivo. Histopathological analyses of skin specimens from human volunteers experimentally exposed to sand fly bites revealed that HO-1 and Nrf2 are produced at bite sites in the skin. These results were recapitulated in mice ears injected with a salivary gland sonicate (SGS) or exposed to sand fly bites, indicating that vector saliva may be a key factor in triggering HO-1 expression. Resident skin macrophages were the main source HO-1 at 24–48 h after bites. Additionally, assays in vivo after bites and in vitro after stimulation with saliva both demonstrated that HO-1 production by macrophages was Nrf2-dependent. Collectively, our data demonstrates that vector saliva induces early HO-1 production at the bite sites, representing a major event associated with establishment of naturally-transmitted Leishmania infections.
Highlights
The leishmaniases are a group of diseases caused by protozoan parasites from more than 20 Leishmania species [1]
Having previously demonstrated that heme oxygenase-1 (HO-1) is induced during Leishmania infection and identified its association with active VL [21], we asked whether it plays a part in the early stages of parasite establishment after vector-transmission
Immunohistochemistry of paraffin-embedded skin sections, obtained 48 h after the last of several experimental exposures of human volunteers to sand fly bites, revealed that both HO-1 (Figures 1A,B and Supplemmentary Figure 1A) and nuclear factor erythroid 2-related factor-2 (Nrf2) (Figures 1C,D, Supplemmentary Figure 1B) were produced in the dermis in situ. Expression of both HO-1 and Nrf2 was not detected in control specimens of skin not bitten by sand flies taken from the same individuals (Figures 1E,F)
Summary
The leishmaniases are a group of diseases caused by protozoan parasites from more than 20 Leishmania species [1]. L. major coinjected with Lutzomyia longipalpis or Phlebotomus papatasi saliva resulted in a more severe disease reflected by larger lesions when compared with a group of mice receiving parasites alone [7]. This initial observation was supported by additional studies demonstrating the enhanced infectivity of L. major when coinoculated with saliva from the sand fly L. longipalpis [8, 9]. It has been proposed that such effects on the host immune system contribute to increased parasite loads in mice exposed to sand fly bites compared to animals infected through needle injection [3]. The specific mechanism underlying the effect of vector saliva on the host immune response is not fully understood
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