DEVELOPMENTAL BIOLOGY OF LEISHMANIA PROMASTIGOTES

在利什曼原虫的自然传播过程中， 蝇类有少量的后环前鞭毛体，沿着 唾液进入哺乳动物宿主的皮肤此前有 唾液可以增强利什曼原虫的传染性。最 然而，生活在流行地区的人暴露于 未感染的苍蝇在叮咬传播感染之前的唾液。 我们试图建立一种皮肤利什曼病模型 在模拟这些自然感染条件的小鼠中： 后环前鞭毛体的数量（103），接种到耳中 真皮，并与来自天然 载体帕帕他西变形杆菌（P. papatasi）接种至未接种小鼠或预先暴露于 口水我们的研究揭示了一个戏剧性的加剧影响唾液 皮肤部位的病变发展。皮肤损伤出现在 更早，发展到更大的尺寸，更具破坏性， 寄生虫的数量更多。疾病恶化是 与唾液引起早期增加（6小时）的能力相关。 在细胞中产生2型细胞因子的细胞频率中， 表皮此外，未观察到加重效应， IL-4敲除。唾液加剧皮肤损伤的能力 在之前注射过的小鼠中被完全废除 唾液腺裂解物。这些老鼠制造了抗唾液抗体 它们被证明可以中和唾液 感染并在表皮中引起2型反应。这些 结果引入了这样的概念，即个人的暴露史 传播唾液会影响感染的结果， 利什曼原虫很少有成功传播到 实验动物咬，几乎没有人探索过 启动宿主对白蛉的炎症和免疫反应 感染.一种可重复的小鼠耳模型， 传播L.大咬一口成立了。该模型 用于研究宿主预敏化对白蛉的影响 唾液通过暴露于未感染的沙蝇叮咬的过程中， 感染皮肤损伤的数量更多， 通过直径和厚度测量病变的进展， 在实验小鼠中的速度明显更快。早期的初步分析 真皮对感染苍蝇叮咬的反应显示， 产生2型的表皮细胞数量急剧增加 细胞因子，尤其是IL-5。这种反应是 在预先暴露于沙蝇叮咬的小鼠中消除，进一步支持 这些细胞因子在唾液引起的疾病恶化中的作用。 尽管L.热带作为一个广泛的原因， 分布的，高度地方性的皮肤利什曼病， 旧世界，没有涉及L. Tropica已经 报道一个实验室群体的白蛉sergenti，这是 L.的天然载体热带传输，成功地 建立，并用于揭示高度的特异性， 向量容量L. tropica sp. vs.其他利什曼原虫菌株。 这一发现具有重要的流行病学意义。

During the natural transmission of Leishmania, sand flies inoculate low numbers of metacyclic promastigotes, along with saliva, into the skin of the mammalian host. It was previously shown that saliva can enhance the infectivity of Leishmania. Most individuals who live in endemic areas, however, are exposed to saliva from uninfected flies before the bite that transmits infection. We have attempted to establish a model of cutaneous leishmaniasis in the mouse that mimics these natural conditions of infection: low number of metacyclic promastigotes (103), inoculation into the ear dermis, and co-inoculation with salivary lysates from a natural vector, P. papatasi, into naive mice or to mice pre-exposed to saliva. Our studies reveal a dramatic exacerbating effect of saliva on lesion development in the dermal site. The dermal lesions appeared earlier, progressed to a larger size, were more destructive, and contained greater numbers of parasites. Disease exacerbation was associated with the ability of saliva to elicit an early increase (6 hr.) in the frequency of cells producing type 2 cytokines in the epidermis. Furthermore, the exacerbating effect was not seen in IL-4 knockout. The ability of saliva to exacerbate dermal lesions was completely abrogated in mice that had been previously injected with salivary gland lysates. These mice made anti-saliva antibodies that were shown to neutralize the ability of saliva to enhance infection and to elicit type 2 responses in the epidermis. These results introduce the notion that the exposure history of individuals to vector saliva will influence the outcome of infection with Leishmania. There are few reports of successful transmission to experimental animals by bite, and virtually none have explored the host inflammatory and immune response to sand fly initiated infections. A reproducible murine ear model based on the transmission of L. major by bite was established. The model was used to investigate the effect of host presensitization to sand fly saliva via exposure to uninfected sand fly bites on the course of infection. The number of dermal lesions produced was greater, and the progression of lesions, measured by diameter and thickness, was significantly faster in naive mice. Preliminary analyses of the early response in the dermis to the bites of infected flies revealed a dramatic increase in the number of epidermal cells producing type 2 cytokines, especially IL-5, in BALB/c. This response was eliminated in mice pre-exposed to sand fly bites, further supporting a role for these cytokines in the exacerbation of disease by saliva. Despite the importance of L. tropica as the cause of a widely distributed, highly endemic form of cutaneous leishmaniasis in the Old World, no vector studies involving L. tropica have been reported. A laboratory colony of Phlebotomus sergenti, which is the natural vector of L. tropica transmission, was successfully established, and used to reveal a high degree of specificity in vectorial capacity for L. tropica sp. vs. other Leishmania strains. This finding has important epidemiologic considerations.