Discovery & characterization of human monoclonal antibodies targeting multiple arthritogenic alphaviruses

发现

基本信息

批准号：
10066764
负责人：
Ryan J Malonis
金额：
$ 5.05万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-22 至 2023-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066764
关键词：
Acute Adaptive Immune System Address Aedes Alphavirus Alphavirus Infections Anopheles Genus Antibodies Antibody Repertoire Antibody Response Antibody Therapy Antiviral Agents Antiviral Therapy Arthritogenic B-Lymphocytes Binding Biochemical Caribbean region Cell Separation Cells Chikungunya virus Chronic Culicidae Development Disease Encephalopathies Endemic Diseases Epidemic Epitope Mapping Epitopes Escape Mutant Exanthema Fever Flow Cytometry Future Hemorrhage Human Immune response Immune system Immunotherapy Infection Kinetics Knowledge Mayaro virus Mediating Monoclonal Antibodies Mus Myalgia Pathogenicity Patients Phase Polyarthralgias Polyarthritides Prevention therapy RNA Viruses Reporting Rheumatism Ross river virus Semliki forest virus Sindbis Virus Site South America Structure Testing Therapeutic Vaccine Design Vaccines Viral Virus chikungunya chikungunya infection combat cross reactivity experimental study human monoclonal antibodies human pathogen in vitro testing infectious disease treatment insight interest mortality mosquito-borne neutralizing antibody neutralizing monoclonal antibodies new therapeutic target novel novel therapeutic intervention pathogen response viral transmission

项目摘要

Project Summary Alphaviruses are enveloped, positive sense single-stranded RNA viruses, which include several important human pathogens. Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause human rheumatic disease and include chikungunya virus (CHIKV) and Mayaro virus (MAYV). Symptomatic infection is characterized by fever, rash, myalgia, as well as both acute and chronic polyarthralgia that can persist for months to years after infection. More severe manifestations of alphaviral disease – including hemorrhage, encephalopathy and mortality – have been reported. These viruses cause endemic disease as well as large, sporadic epidemics worldwide. Currently, there are no approved vaccines or anti-viral therapies for the prevention or treatment of alphavirus infection; therefore, the development of new therapeutic strategies targeting one or multiple arthritogenic alphaviruses is of substantial interest. A number of potently neutralizing CHIKV monoclonal antibodies (mAbs) have been described, but currently the only broadly neutralizing alphavirus mAbs that have been reported are murine. Thus, the extent to which the human antibody response elicits broadly-neutralizing mAbs following alphavirus infection, and which epitope(s) such mAbs may target, remains unknown. To address this question, this proposal seeks to expand our knowledge of the neutralizing antibody response to alphaviruses by systematically investigating cross- reactive antibodies from CHIKV-infected patients. Towards this end, we have used single B cell sorting to isolate a large panel of MAYV-reactive mAbs from CHIKV patients in the convalescent phase. We will study the reactivity and neutralization profiles of these mAbs against related arthitogenic alphaviruses (Aim 1). We will then biochemically determine the requirements of neutralization (Aim 2) and elucidate the mechanism of mAb inhibition (Aim 3). These studies will contribute to our fundamental understanding of how the adaptive immune system combats infection by arthritogenic alphaviruses and may aid the development of novel mAb- based treatments and vaccines.

项目概要甲病毒是有包膜的正义单链 RNA 病毒，包括多种重要的人类病原体。致关节炎甲病毒是全球分布的、通过蚊子传播的病毒。引起人类风湿病的病毒包括基孔肯雅病毒 (CHIKV) 和马亚罗病毒 (MAYV)。有症状感染的特点是发烧、皮疹、肌痛以及急性和慢性多关节痛感染后可能会持续数月至数年。包括出血、脑病和死亡——已有报道称这些病毒会导致地方性流行。目前，尚无批准的疫苗或抗病毒药物。用于预防或治疗甲病毒感染的疗法；因此，开发新的治疗方法针对一种或多种致关节炎甲病毒的策略引起了人们的极大兴趣。已经描述了许多有效中和 CHIKV 单克隆抗体 (mAb)，但是目前，唯一报道的广泛中和甲病毒单克隆抗体是鼠源的。甲病毒感染后，人类抗体反应会引发广泛中和的单克隆抗体，并且这种单克隆抗体可能针对的表位仍然未知。为了解决这个问题，本提案试图扩大范围。通过系统地研究交叉病毒，我们了解了对甲病毒的中和抗体反应为此，我们使用单 B 细胞分选来检测 CHIKV 感染患者的反应性抗体。我们将研究从恢复期的 CHIKV 患者中分离出大量 MAYV 反应性单克隆抗体。这些单克隆抗体针对相关致关节炎甲病毒的反应性和中和特性（目标 1）。然后将通过生化方法确定中和的要求（目标 2）并阐明中和的机制 mAb 抑制（目标 3）。这些研究将有助于我们对适应性如何产生基本了解。免疫系统对抗致关节炎甲病毒的感染，并可能有助于新型单克隆抗体的开发基于治疗和疫苗。