Discovery & characterization of human monoclonal antibodies targeting multiple arthritogenic alphaviruses

发现

• 批准号: 10445303
• 负责人: Ryan J Malonis
• 金额: $ 4.81万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445303
• 关键词: Acute; Adaptive Immune System; Address; Aedes; Alphavirus; Alphavirus Infections; Anopheles Genus; Antibodies; Antibody Repertoire; Antibody Response; Antibody Therapy; 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; 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 感染后可能持续数月至数年。甲病毒病更严重的表现 - 包括出血、脑病和死亡——已有报道。这些病毒引起地方病 疾病以及世界范围内大规模、零星的流行病。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抗体。因此，程度到 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靶向的表位仍然未知。为了解决这个问题，本提案旨在扩大 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 来自 CHIKV 感染患者的反应性抗体。为此，我们使用单个 B 细胞分选来 从恢复期的 CHIKV 患者中分离出大量 MAYV 反应性单克隆抗体。我们将学习 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）。我们 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从根本上理解适应性如何 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。

项目成果

Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.

• DOI: 10.1371/journal.pcbi.1009778
• 发表时间: 2022-01
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Lasso G;Khan S;Allen SA;Mariano M;Florez C;Orner EP;Quiroz JA;Quevedo G;Massimi A;Hegde A;Wirchnianski AS;Bortz RH 3rd;Malonis RJ;Georgiev GI;Tong K;Herrera NG;Morano NC;Garforth SJ;Malaviya A;Khokhar A;Laudermilch E;Dieterle ME;Fels JM;Haslwanter D;Jangra RK;Barnhill J;Almo SC;Chandran K;Lai JR;Kelly L;Daily JP;Vergnolle O
• 通讯作者: Vergnolle O

Single-Dilution COVID-19 Antibody Test with Qualitative and Quantitative Readouts.

• DOI: 10.1128/msphere.00224-21
• 发表时间: 2021-04-21
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Bortz RH 3rd;Florez C;Laudermilch E;Wirchnianski AS;Lasso G;Malonis RJ;Georgiev GI;Vergnolle O;Herrera NG;Morano NC;Campbell ST;Orner EP;Mengotto A;Dieterle ME;Fels JM;Haslwanter D;Jangra RK;Celikgil A;Kimmel D;Lee JH;Mariano MC;Nakouzi A;Quiroz J;Rivera J;Szymczak WA;Tong K;Barnhill J;Forsell MNE;Ahlm C;Stein DT;Pirofski LA;Goldstein DY;Garforth SJ;Almo SC;Daily JP;Prystowsky MB;Faix JD;Fox AS;Weiss LM;Lai JR;Chandran K
• 通讯作者: Chandran K