Delayed-Type Hypersensitivity to Sand Fly Saliva in Humans from a Leishmaniasis-Endemic Area of Mali Is TH1-Mediated and Persists to Midlife

Abstract

Immunity to sand fly saliva in rodents induces a TH1 delayed-type hypersensitivity (DTH) response conferring protection against leishmaniasis. The relevance of DTH to sand fly bites in humans living in a leishmaniasis-endemic area remains unknown. Here, we describe the duration and nature of DTH to sand fly saliva in humans from an endemic area of Mali. DTH was assessed at 24, 48, 72, and 96 hours post bite in volunteers exposed to colony-bred sand flies. Dermal biopsies were obtained 48 hours post bite; cytokines were quantified from peripheral blood mononuclear cells (PBMCs) stimulated with sand fly saliva in vitro. A DTH response to bites was observed in 75% of individuals aged 1–15 years, decreasing gradually to 48% by age 45, and dropping to 21% thereafter. Dermal biopsies were dominated by T lymphocytes and macrophages. Abundant expression of IFN-γ and absence of TH2 cytokines establishes the TH1 nature of this DTH response. PBMCs from 98% of individuals responded to sand fly saliva. Of these, 23% were polarized to a TH1 and 25% to a TH2 response. We demonstrate the durability and TH1 nature of DTH to sand fly bites in humans living in a cutaneous leishmaniasis-endemic area. A systemic TH2 response may explain why some individuals remain susceptible to disease.

Human cellular and humoral immune responses to Phlebotomus papatasi salivary gland antigens in endemic areas differing in prevalence of Leishmania major infection

“…longipalpis or P . duboscqi bites, was previously reported in individuals wether after experimental or natural exposure [24,30,31]. An increase in the frequency of T CD4+ and T CD8+ cells, with IFN-γ and IL-10 production were described in PBMC from human volunteers experimentally exposed to L .…”

“…major infection in animal models [25–29]. DTH to sand fly bites was also described in humans [24,30] and more recently in a cutaneous leishmaniasis (CL) endemic area where it was shown to be Th1-mediated [31]. However, effects of sand fly saliva during natural exposure of individuals in leishmaniasis endemic areas, on modulation of parasite-specific immune response and outcome of infection, are not clearly understood.…”

A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates

“…PdSP15 is immunogenic in humans naturally exposed to P. duboscqi bites Having established that PdSP15 is an antigen foreign to humans, we investigated the immunogenicity of rPdSP15 in individuals naturally exposed to P. duboscqi bites (13). Sand fly-exposed individuals with antibodies to whole saliva produced significant levels of antibodies to rPdSP15 (P < 0.0001, Mann-Whitney test; n = 12 to 30; Fig.…”

“…Indeed, only 50% of human subjects experimentally exposed to bites of Lutzomyia longipalpis sand flies presented with nodules indicative of a DTH response (34). Moreover, 23 and 25% of PBMCs from individuals inhabiting an endemic area of CL in central Mali where P. duboscqi is the main vector of L. major (35) displayed a T H 1-or T H 2-polarized response upon stimulation with whole saliva of P. duboscqi, and 52% presented with a mixed response (13). The factors underlying the absence or diversity of the cellular immune response against sand fly salivary proteins in some humans and NHP remain to be elucidated and may be of importance in determining who in endemic areas are likely to contract CL.…”

Mechanisms of cellular invasion by intracellular parasites

“…Interestingly, pre-exposure to sand fly saliva has been shown to be protective to subsequent leishmania infection[25, 26], bringing forth the possibility is using saliva components as a vaccine[27–31]. Work is ongoing in order to understand how the responses to saliva protect against leishmaniasis or if the results of these studies in mice are applicable to humans[32]. …”