Host and parasite determinants of Leishmania Viannia persistence in naturally infected human populations

项目摘要 利什曼原虫引起的人类皮肤利什曼病的自然史 提供了明确的证据，表明寄生虫在无症状以及 感染的人。持续性感染可以保持无症状，也可以 临床表现为粘膜或皮肤利什曼病（ML和CL）的发展 在无症状感染后，或作为原发性疾病消退后很长时间的复发性疾病 病变结膜、鼻和口咽部持续寄生虫的分子证据 粘膜组织、皮肤和血液单核细胞已经记录在多达40%的感染者中， 在L.不过Viannia的传播有宿主免疫的作用 反应和寄生虫亚群促进和维持利什曼原虫的持久性， 人类仍然未知。免疫耐受也是一个潜在因素， 潜伏感染和组织保护的感染，由其他原生动物，如疟原虫， 弓形虫类似的宿主免疫耐受机制可能有助于利什曼原虫 在没有体征和症状的情况下持续存在，因为免疫稳态被破坏， 免疫抑制或局部创伤已被确定为复发性CL的促成因素。我们 假设利什曼原虫与宿主的相互作用引发了强大但受调节的先天免疫， 免疫应答驱动免疫耐受的局部环境的建立（代谢和 免疫学），有利于利什曼原虫在人类中的持久性。 在这个项目中，我们将描述转录组，代谢组和免疫表型 与持续感染有关的宿主组织和细胞的。我们将对相应的 利什曼原虫种群，并将评估免疫耐受的参与， 已检测到利什曼原虫持续存在的组织：鼻粘膜、皮肤和单核细胞。 更具体地说，我们将1）确定利什曼原虫在队列中持续存在的分子特征 2）描述持续性CL的基因型和表型 利什曼原虫亚群，因为它们调节人宿主细胞，和3）扩增离体3D细胞 建立利什曼原虫代谢和免疫微环境模型的培养系统 持久性。该项目将提供关于代谢和免疫的关键知识， 人体组织的微环境允许利什曼原虫的持久性，定义签名 和生物标志物的持久性，并推进离体模型的持续性利什曼原虫感染。

Project Summary The natural history of human dermal leishmaniasis caused by Leishmania Viannia species provides unequivocal evidence of long-term persistence of parasites in asymptomatically as well as symptomatically infected individuals. Persistent infection can remain asymptomatic, or can be clinically manifested through the development of mucosal or cutaneous leishmaniasis (ML and CL) following either asymptomatic infections, or as recurrent disease long after resolution of primary lesions. Molecular evidence of persistent parasites in the conjunctiva, nasal and oropharyngeal mucosal tissues, skin and blood monocytes has been documented in as many as 40% of infected individuals in endemic areas of L. Viannia transmission, however, the role of the host immune response and parasite subpopulations in promoting and sustaining Leishmania persistence in humans remains unknown. It is also well established that immune tolerance is an underlying factor of latent infection and tissue protection in infections by other protozoa such as Plasmodium and Toxoplasma. Similar host mechanisms of immune tolerance likely contribute to Leishmania persistence in the absence of signs and symptoms, since disruption of the immune homeostasis by immunosuppression or local trauma have been identified as contributing factors in recurrent CL. We hypothesize that Leishmania-host interactions eliciting strong, yet regulated innate immune responses drive the establishment of local environments of immune tolerance (metabolic and immunological), that favor Leishmania persistence in humans. In this project we will characterize the transcriptomes, metabolomes and immunophenotypes of host tissues and cells associated with persistent infection. We will genotype the corresponding Leishmania populations, and will assess the participation of immunological tolerance in human tissues where Leishmania persistence has been detected: nasal mucosa, skin and monocytes. More specifically, we will 1) Identify the molecular signature of Leishmania persistence in a cohort of patients with prior history of CL, 2) Characterize the genotype and phenotype of persister Leishmania sub-populations as they modulate human host cells, and 3) Expand an ex vivo 3D cell culture system to model the metabolic and immunological microenvironment of Leishmania persistence. This project will provide critical knowledge on the metabolic and immunological microenvironments of human tissues permissive for Leishmania persistence, define the signatures and biomarkers of persistence, and advance ex vivo models of persistent Leishmania infection.