Discovery & characterization of human monoclonal antibodies targeting multiple arthritogenic alphaviruses

发现

• 批准号: 10300991
• 负责人: Ryan J Malonis
• 金额: $ 5.1万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/10300991
• 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; cross reactivity; emerging pathogen; 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; response; viral transmission

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.

项目摘要 α病毒是包裹的，积极的单链RNA病毒，其中包括几种 重要的人类病原体。关节炎α病毒是全球分布的，蚊子传播病毒 这会引起人类风湿病，包括Chikungunya病毒（Chikv）和Mayaro病毒（Mayv）。 有症状的感染的特征是发烧，皮疹，肌痛以及急性和慢性多腹痛 感染后几个月至数年。阿phaviral疾病的更严重的表现 - 包括出血，脑病和死亡率，已有报道。这些病毒引起内在 疾病以及大型零星发作。目前，没有批准的疫苗或抗病毒 预防或治疗α病毒感染的疗法；因此，新治疗的发展 针对一种或多种肺炎α病毒的策略具有很大的兴趣。 已经描述了许多潜在的中和Chikv单克隆抗体（mAb），但 目前，据报道的唯一广泛中和α病毒mAB是鼠。那是 人类抗体反应在α感染后广泛地中和mAb，并且 这种mAb可能靶向的表位仍然未知。为了解决这个问题，该提议旨在扩大 我们通过系统地研究交叉的了解对α病毒的中和抗体反应的了解 CHIKV感染患者的反应性抗体。为此，我们使用了单个B细胞分类 分离康复期CHIKV患者的一大批Mayv反应性mAb。我们将学习 这些mAb对相关艺术α病毒的反应性和神经仿真谱（AIM 1）。我们 然后将在生化确定中和的要求（AIM 2）并阐明 mAb抑制（目标3）。这些研究将有助于我们对适应性的基本理解 免疫系统通过关节炎α病毒打击感染，并可能有助于发展新型mab- 基于治疗和疫苗。