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Discovery & characterization of human monoclonal antibodies targeting multiple arthritogenic alphaviruses

发现

基本信息

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
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/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

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.

项目总结