Mechanisms of Parasite Dissemination in Visceral Leishmaniasis

内脏利什曼病是由细胞内原生动物杜氏利什曼原虫或婴儿利什曼原虫引起的 影响世界穷人的“被忽视的热带病”。当寄生虫被感染时，人就会被感染 在沙蝇媒介的血餐过程中沉积在真皮中。大多数被感染的人 发展为潜伏感染，而不是临床疾病。然而，一些人会患上慢性进行性疾病 感染的特征是发烧、恶病质、大量脾肿大、全血细胞减少并最终死亡。这个 寄生虫经皮肤传播的机制及仅有少数感染者的原因 发生全面疾病的原因尚不清楚，但营养不良已被确定为 活动性疾病的发展。VL发病机制的研究进展受阻于 缺乏适合研究寄生虫从皮肤接种部位传播的模型。这项研究 这里提出将使用临床相关的动物宿主(营养不良的小鼠)和自然寄生虫传播 通过被感染的沙蝇的叮咬来确定导致VL的寄生虫传播机制。我们的中央 假设寄生虫的传播是由改变的皮肤炎症和髓系细胞介导的 将寄生虫从皮肤传播到内脏器官。我们公布的和初步的数据表明，有三个- 寄生虫传播的组成部分模型，涉及(1)炎性细胞增加流入 寄生虫进入皮肤；(2)受感染的髓系细胞(主要是单核细胞和中性粒细胞)的过度迁移 从皮肤，以及(3)迁移感染的髓系细胞从引流淋巴中逃逸的增加。我们 建议营养不良和病媒相关炎症共存，就像在美国流行地区一样 它将协同促进寄生虫的传播和活跃的VL。在具体目标1中，我们将确定 针刺感染皮肤后早期髓系细胞募集和寄生虫归宿的动态变化 媒介传播。我们的工作假设是，失调的皮肤炎，对 营养不良或沙蝇喂养，推动了髓系细胞运输和病原体捕获的改变 皮肤。特别是，我们将确定炎症调节失调如何导致中性粒细胞的差异。 以及炎性单核细胞流入、寄生虫捕获和细胞从皮肤流出。在具体目标2中，我们将 确定髓系细胞转运和杜氏杆菌从皮肤到内脏传播的机制 针头注射和媒介传播后的器官。我们的工作假说是髓系细胞增多 通过传入淋巴管的运输，加上引流层中细胞滞留的减少，导致寄生虫 传播。炎症介质和趋化因子及其受体的变化可能是 寄生虫传播到内脏器官。了解寄生虫内脏作用背后的机制可以 采取干预措施，减少寄生虫传播和发展这一毁灭性疾病的风险。

Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani or L. infantum, is one of the “Neglected Tropical Diseases” that impacts the poor of the world. People are infected when the parasite is deposited in the dermis during the bloodmeal of the sand fly vector. The majority of people who are infected develop a latent infection without clinical disease. However, some individuals develop a chronic progressive infection characterized by fever, cachexia, massive splenomegaly, pancytopenia and ultimately death. The mechanism of parasite dissemination from the skin and the reason that only a minority of infected individuals develop full-blown disease are not understood, but malnutrition has been identified as a major risk factor for the development of active disease. Progress in understanding the pathogenesis of VL has been hindered by the lack of models suitable for study of parasite dissemination from the site of skin inoculation. The research proposed here will use a clinically relevant animal host (malnourished mice) and natural parasite transmission by the bite of an infected sand fly to define the mechanisms of parasite dissemination that lead to VL. Our central hypothesis is that parasite dissemination is driven by altered cutaneous inflammation and myeloid cell-mediated trafficking of the parasite from the skin to visceral organs. Our published and preliminary data suggest a three- component model of parasite dissemination that involves (1) increased influx of inflammatory cells to the site of parasite entry in the skin; (2) hyper-migration of infected myeloid cells (primarily monocytes and neutrophils) from the skin, and (3) increased escape of migrating infected myeloid cells from the draining lymph node. We propose that co-existent malnutrition- and vector-related inflammation, as would occur in endemic regions of the world, will synergistically promote parasite dissemination and active VL. In Specific Aim 1 we will determine the dynamics of early myeloid cell recruitment and parasite fate in the skin following infection by needle injection and vector-transmission. Our working hypothesis is that dysregulated cutaneous inflammation, in response to malnutrition or sand fly feeding, drives the altered dynamics of myeloid cell trafficking and pathogen capture in the skin. In particular, we will determine how the dysregulated inflammation leads to differences in neutrophil and inflammatory monocyte influx, parasite capture, and cell egress from the skin. In Specific Aim 2 we will determine the mechanisms of myeloid cell trafficking and L. donovani dissemination from the skin to visceral organs following needle injection and vector-transmission. Our working hypothesis is that increased myeloid cell trafficking through the afferent lymphatic, coupled with reduced cell retention in the draining LN, leads to parasite dissemination. Changes in inflammatory mediators and chemokines and their receptors are likely to underpin parasite trafficking to the visceral organs. Understanding the mechanisms behind parasite visceralization can lead to interventions to reduce the risk for parasite dissemination and development of this devastating disease.