Protection Against Cutaneous Leishmaniasis Resulting from Bites of Uninfected Sand Flies
17 Nov 2000-Science (American Association for the Advancement of Science)-Vol. 290, Iss: 5495, pp 1351-1354
TL;DR: Prior exposure of mice to bites of uninfected sand flies conferred powerful protection against Leishmania major that was associated with a strong delayed-type hypersensitivity response and with interferon-gamma production at the site of parasite delivery.
Abstract: Despite the fact that Leishmania are transmitted exclusively by sand flies, none of the experimental models of leishmaniasis have established infection via sand fly bites. Here we describe a reproducible murine model of Leishmania major infection transmitted by Phlebotomus papatasi. Prior exposure of mice to bites of uninfected sand flies conferred powerful protection against Leishmania major that was associated with a strong delayed-type hypersensitivity response and with interferon-gamma production at the site of parasite delivery. These results have important implications for the epidemiology of cutaneous leishmaniasis and suggest a vaccination strategy against this and possibly other vector-borne diseases.
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TL;DR: I. Foldamer Research 3910 A. Backbones Utilizing Bipyridine Segments 3944 1.
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1,922 citations
TL;DR: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major — involving the early production of interleukin-4 by a small subset of LeishMania-specific CD4+ T cells — have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility.
Abstract: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major -- involving the early production of interleukin-4 by a small subset of Leishmania-specific CD4+ T cells -- have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility. In addition, more recent studies in L. major-resistant mice have revealed complexities in the mechanisms responsible for acquired immunity, which necessitate the redesign of vaccines against Leishmania and other pathogens that require sustained cell-mediated immune responses.
1,136 citations
TL;DR: Infection with the obligate intracellular protozoan Leishmania major (L.m.m.) appears to have evolved to both evade and exploit the innate host response to sand fly bite in order to establish and promote disease.
Abstract: Infection with the obligate intracellular protozoan Leishmania is thought to be initiated by direct parasitization of macrophages, but the early events following transmission to the skin by vector sand flies have been difficult to examine directly. Using dynamic intravital microscopy and flow cytometry, we observed a rapid and sustained neutrophilic infiltrate at localized sand fly bite sites. Invading neutrophils efficiently captured Leishmania major (L.m.) parasites early after sand fly transmission or needle inoculation, but phagocytosed L.m. remained viable and infected neutrophils efficiently initiated infection. Furthermore, neutrophil depletion reduced, rather than enhanced, the ability of parasites to establish productive infections. Thus, L.m. appears to have evolved to both evade and exploit the innate host response to sand fly bite in order to establish and promote disease.
744 citations
TL;DR: A novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease is suggested as sterile cure was achieved in IL-10–deficient and IL-4/IL-10 double-deficient mice.
Abstract: Some pathogens (e.g., Mycobacterium tuberculosis, Toxoplasma gondii, Leishmania spp) have been shown to persist in their host after clinical cure, establishing the risk of disease reactivation. We analyzed the conditions necessary for the long term maintenance of Leishmania major in genetically resistant C57BL/6 mice after spontaneous healing of their dermal lesions. Interleukin (IL)-10 was found to play an essential role in parasite persistence as sterile cure was achieved in IL-10–deficient and IL-4/IL-10 double-deficient mice. The requirement for IL-10 in establishing latency associated with natural infection was confirmed in IL-10–deficient mice challenged by bite of infected sand flies. The host-parasite equilibrium was maintained by CD4+ and CD8+ T cells which were each able to release IL-10 or interferon (IFN)-γ, and were found to accumulate in chronic sites of infection, including the skin and draining lymph node. A high frequency of the dermal CD4+ T cells released both IL-10 and IFN-γ. Wild-type mice treated transiently during the chronic phase with anti–IL-10 receptor antibodies achieved sterile cure, suggesting a novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease.
583 citations
Cites background or methods from "Protection Against Cutaneous Leishm..."
...major in the skin after healing of dermal lesions resulting from sand fly challenge has recently been demonstrated (20)....
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...Flies were infected by artificial feeding on a chick membrane at 37 C as described previously (20)....
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TL;DR: The current understanding of the mechanisms that Leishmania parasites use to ensure their transmission from sand fly vectors by bite is reviewed, and the most important mechanism is the creation of a “blocked fly” resulting from the secretion of promastigote secretory gel by the parasites in the anterior midgut.
462 citations
Cites background from "Protection Against Cutaneous Leishm..."
...Another important area of future research is the possible development of anti-saliva vaccines (Kamhawi et al., 2000; Valenzuela et al., 2001; Oliveira et al., 2006)....
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...Another important area of future research is the possible development of anti-saliva vaccines (Kamhawi et al., 2000; Valenzuela et al., 2001; Oliveira et al., 2006)....
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References
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TL;DR: The role of sand fly saliva in transmission of the disease was investigated by injecting mice with Leishmania major parasites in the presence of homogenized salivary glands from Lutzomyia longipalpis, resulting in cutaneous lesions that were routinely five to ten times as large and contained as much as 5000 times as many parasites as controls.
Abstract: Leishmaniasis is a parasitic disease transmitted by phlebotomine sand flies. The role of sand fly saliva in transmission of the disease was investigated by injecting mice with Leishmania major parasites in the presence of homogenized salivary glands from Lutzomyia longipalpis. This procedure resulted in cutaneous lesions of Leishmania major that were routinely five to ten times as large and contained as much as 5000 times as many parasites as controls. With inocula consisting of low numbers of Leishmania major, parasites were detected at the site of injection only when the inoculum also contained salivary gland material. This enhancing effect of sand fly salivary glands on cutaneous leishmaniasis occurred with as little as 10 percent of the contents of one salivary gland of one fly. Material obtained from other bloodsucking arthropods could not mediate the phenomenon.
469 citations
TL;DR: The studies reveal a dramatic exacerbating effect of SGS on lesion development in the dermal site, and a complete abrogation of this effect in mice preexposed to salivary components, the first to suggest that for individuals at risk of vector-borne infections, history of exposure to vector saliva might influence the outcome of Exposure to transmitted parasites.
Abstract: We have developed a model of cutaneous leishmaniasis due to Leishmania major that seeks to mimic the natural conditions of infection. 1,000 metacyclic promastigotes were coinoculated with a salivary gland sonicate (SGS) obtained from a natural vector, Phlebotomus papatasii, into the ear dermis of naive mice or of mice preexposed to SGS. The studies reveal a dramatic exacerbating effect of SGS on lesion development in the dermal site, and a complete abrogation of this effect in mice preexposed to salivary components. In both BALB/c and C57Bl/6 (B/6) mice, the dermal lesions appeared earlier, were more destructive, and contained greater numbers of parasites after infection in the presence of SGS. Furthermore, coinoculation of SGS converted B/6 mice into a nonhealing phenotype. No effect of SGS was seen in either IL-4- deficient or in SCID mice. Disease exacerbation in both BALB/c and B/6 mice was associated with an early (6 h) increase in the frequency of epidermal cells producing type 2 cytokines. SGS did not elicit type 2 cytokines in the epidermis of mice previously injected with SGS. These mice made antisaliva antibodies that were able to neutralize the ability of SGS to enhance infection and to elicit IL-4 and IL-5 responses in the epidermis. These results are the first to suggest that for individuals at risk of vector-borne infections, history of exposure to vector saliva might influence the outcome of exposure to transmitted parasites.
426 citations
TL;DR: The results extend to a natural infection model a role for Th1 cells in both acquired resistance and lesion formation, and document the remarkable avoidance of this response during a prolonged phase of parasite amplification in the skin.
Abstract: A model of Leishmania major infection in C57BL/6 mice has been established that combines two main features of natural transmission: low dose (100 metacyclic promastigotes) and inoculation into a dermal site (the ear dermis). The evolution of the dermal lesion could be dissociated into two distinct phases. The initial “silent” phase, lasting 4–5 wk, favored establishment of the peak load of parasites in the dermis in the absence of lesion formation or any overt histopathologic changes in the site. The second phase corresponds to the development of a lesion associated with an acute infiltration of neutrophils, macrophages, and eosinophils into the dermis and was coincident with the killing of parasites in the site. The onset of immunity/pathology was correlated with the appearance of cells staining for IL-12p40 and IFN-γ in the epidermal compartment, and an expansion of T cells capable of producing IFN-γ in the draining lymph node. Parasite growth was not enhanced over the first 4.5 wk in anti-CD4-treated mice, SCID mice, or C57BL/6 mice deficient in IL-12p40, IFN-γ, CD40 ligand, or inducible NO synthase. These mice all failed to ultimately control infection in the site, but in some cases (anti-CD4 treated, IL-12p40−/−, CD40 ligand−/−, and SCID) high dermal parasite loads were associated with little or no pathology. These results extend to a natural infection model a role for Th1 cells in both acquired resistance and lesion formation, and document the remarkable avoidance of this response during a prolonged phase of parasite amplification in the skin.
377 citations
TL;DR: Tick-induced host immunosuppression facilitates blood meal acquisition and is an important factor in the transmission/establishment of the tick-borne disease-causing agent, Borrelia burgdorferi.
276 citations
Journal Article•
TL;DR: Results indicate that epidermal LC, in particular cultured LC maturing into dendritic cells, express IL-12 p40 mRNA, as well as p40 and functional p70 protein, and suggest that this is one mechanism behind the high potency of dendrite APCs, such as LC, to initiate Th1 type immune responses under appropriate conditions.
Abstract: IL-12 is a 70-kDa heterodimeric cytokine composed of a p35 chain and p40 chain. This cytokine exerts a powerful positive regulatory influence on the development of Th1 helper T-cell immune responses and is a potent inducer of IFN-gamma production and cytotoxic T cell differentiation and function. Because epidermal Langerhans cells (LC) are important members of the dendritic APC lineage family critical for initiating cell mediated immune responses, we examined LC for their ability to produce IL-12. Epidermal cell (EC) suspensions obtained from volunteers were enriched for, or depleted of, Langerhans cells (CD1a+ EC). Enriched populations contained > 90% CD1a+ cells, whereas depleted populations contained < 1% CD1a+ cells. As assessed by reverse transcription-PCR amplification, IL-12 p40 mRNA was constitutively expressed in LC RNA extracted immediately following keratome harvest, and increased spontaneously after overnight incubation. Radioimmunoassay (RIA) of IL-12 p40 protein on supernatants revealed IL-12 release by CD1a-enriched fractions of epidermal cells. Ab specific for p40 clearly demonstrated IL-12 in epidermal LC by flow cytometry. A bioassay for the functional IL-12 heterodimer (p70) indicated that LC could produce IL-12 biologic activity, which was neutralized by anti-IL-12 Ab. These results indicate that epidermal LC, in particular cultured LC maturing into dendritic cells, express IL-12 p40 mRNA, as well as p40 and functional p70 protein, and suggest that this is one mechanism behind the high potency of dendritic APCs, such as LC, to initiate Th1 type immune responses under appropriate conditions.
180 citations