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

利什曼原虫在自然感染人群中持续存在的宿主和寄生虫决定因素

• 批准号: 10569347
• 负责人: Najib M El-Sayed
• 金额: $ 62.25万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-28 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569347
• 关键词: 3-Dimensional; Aftercare; Area; Biological Markers; Blood specimen; Cell Culture System; Cells; Clinical; Cutaneous Leishmaniasis; Development; Disease; Drug Exposure; Drug resistance; Environment; Genotype; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immunologics; Immunophenotyping; Immunosuppression; Individual; Infection; Innate Immune Response; Knowledge; Leishmania; Leishmania viannia; Lesion; Macrophage; Metabolic; Modeling; Molecular; Molecular Profiling; Mucous Membrane; Natural History; Nose; Oropharyngeal; Outcome; Parasites; Participant; Patients; Phenotype; Plasmodium; Population; Primary Lesion; Protozoa; Protozoan Infections; Recording of previous events; Recurrence; Recurrent disease; Resolution; Role; Signs and Symptoms; Skin; Structure of mucous membrane of nose; Symptoms; System; Therapeutic; Tissues; Toxoplasma; Trauma; Treatment Failure; Viannia; chronic infection; cohort; conjunctiva; drug isolation; drug-sensitive; healing; human tissue; in vivo; latent infection; lonely individuals; metabolome; metabolomics; monocyte; peripheral blood; permissiveness; response; three dimensional cell culture; transcriptome; transcriptomics; transmission process; tumor-immune system interactions

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.

项目摘要 利什曼原虫引起的人类皮肤利什曼病的自然历史 提供明确的证据，证明寄生虫在无症状和 有症状的感染者。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) 在无症状感染后，或作为原发症状消失后很久的复发性疾病 损伤。结膜、鼻腔和口咽部持续寄生虫的分子证据 粘膜组织、皮肤和血单核细胞在多达40%的感染者中被记录在案 然而，在流行地区传播华支睾吸虫的个体，宿主免疫的作用 在促进和维持利什曼原虫持久性方面的反应和寄生虫亚群 人类仍然不为人知。免疫耐受也是一个公认的潜在因素。 在其他原生动物感染中的潜伏感染和组织保护 弓形虫。类似的免疫耐受宿主机制可能导致利什曼病 在没有体征和症状的情况下持续存在，因为免疫平衡被破坏 免疫抑制或局部创伤被认为是复发CL的致病因素。我们 假设利什曼原虫与宿主的相互作用能激发强大的、但受调节的先天免疫 应对措施推动了当地免疫耐受环境的建立(代谢和 免疫学)，这有利于利什曼病在人类中的持久性。 在这个项目中，我们将描述转录本、代谢体和免疫表型。 与持续感染相关的宿主组织和细胞。我们将对相应的基因进行分型 利什曼原虫种群，并将评估人类免疫耐受的参与情况 检测到持续利什曼原虫的组织：鼻黏膜、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 有CL既往病史的患者，2)持续期患者的基因和表型特征 利什曼原虫亚群调节人类宿主细胞，以及3)体外扩增3D细胞 模拟利什曼原虫代谢和免疫微环境的培养系统 坚持不懈。该项目将提供代谢和免疫学方面的关键知识。 人体组织微环境允许利什曼原虫持续存在，定义特征 和持久性的生物标记物，并推进持续利什曼原虫感染的体外模型。