Human antibody modification of enterovirus D68 infection

肠道病毒D68感染的人源抗体修饰

• 批准号: 10652557
• 负责人: Matthew R Vogt
• 金额: $ 19.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-21 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652557
• 关键词: Acute; Adult; Affect; Age; Age Months; Air; Antibodies; Antibody Response; Antibody-mediated protection; Apical; B-Lymphocytes; Back; Biological Models; Breathing; Cell Culture Techniques; Cells; Central Nervous System; Central Nervous System Diseases; Cessation of life; Child; Childhood; Circulation; Communicable Diseases; Complement; Cotton Rats; Deglutition; Disease; Disease Outbreaks; Disease model; Enterovirus; Enterovirus 68; Epithelial Cells; Epitopes; Etiology; Family Picornaviridae; Fever; Funding; Future; Gastrointestinal tract structure; Goals; Health; Hour; Human; Human Characteristics; Human poliovirus; Immune response; Immunoglobulins; Immunologics; Immunology; Incidence; Industry Collaboration; Infection; Infection prevention; Inflammation; Intranasal Administration; K-Series Research Career Programs; Kinetics; Limb structure; Liquid substance; Lung; Mentors; Microbiology; Modeling; Modification; Monoclonal Antibodies; Mucous Membrane; Mus; Muscle; Neurological Models; Neuropathogenesis; Newborn Infant; North Carolina; Paralysed; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physicians; Poliomyelitis; Predisposition; Program Development; Recovery; Research; Residual state; Respiratory Disease; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Scientist; Seroprevalences; Serum; Surface; Teenagers; Testing; Therapeutic Agents; Tissue Model; Training; Translating; United States; Universities; Vaccination; Vaccine Design; Vaccines; Viral Pathogenesis; Virus; Virus Diseases; Work; acute flaccid myelitis; airway epithelium; animal model development; career; career development; cross reactivity; efficacy evaluation; emerging pathogen; empowerment; experience; glycosylation; human monoclonal antibodies; human tissue; in vivo; intraperitoneal; medical schools; mouse model; nervous system disorder; neuronal transport; neutralizing antibody; neutralizing monoclonal antibodies; pathogenic virus; permissiveness; polyclonal antibody; preadolescence; prevent; professor; programs; prophylactic; receptor; respiratory; respiratory pathogen; response; seropositive; skill acquisition; targeted treatment; tenure track; tool; transmission process; viral transmission

Project Summary/Abstract Acute flaccid myelitis (AFM) is a poliomyelitis-like illness of children that emerged in the US in 2014. Since then, AFM outbreaks occur August-October every other year, concurrent with outbreaks of enterovirus D68 (EV-D68) infection. Increasing evidence now indicates that EV-D68 is a principal cause of AFM. EV-D68, in the same Enterovirus genus as poliovirus, primarily causes respiratory tract infections. However, the mechanisms of EV-D68 neuropathogenesis and the characteristics of the human immune response to EV-D68 are poorly understood. This five-year research career development award will provide training and development of the skills necessary for the PI to establish an independent research program focused on understanding how EV-D68 causes respiratory and neurologic disease and how human antibodies modify this pathogenesis. Currently the PI is an Assistant Professor on the tenure track in Pediatric Infectious Diseases and Microbiology & Immunology at the University of North Carolina at Chapel Hill School of Medicine. His training to date has focused on the isolation and characterization of human monoclonal antibodies (mAbs) from subjects with prior EV-D68 infection. He will supplement this experience with further training in developing in vivo mouse and ex vivo human tissue models of EV-D68 infection with which to study the pathogenesis of this virus and how human antibodies, both monoclonal and polyclonal, modify pathogenesis. The short-term goal of the proposed studies is to test the central hypothesis that human antibodies prevent EV-D68 from causing AFM but do not protect against respiratory disease. The PI will be mentored by national experts in the study of picornaviruses (Drs. Craig Cameron and Stanley Lemon), human airway epithelial cultures (Dr. Raymond Pickles), mouse models of virus infection (Dr. Mark Heise), and human antibodies (Dr. James Crowe, Jr.). The specific aims are to 1) determine how EV-D68-specific human antibodies modify virus-induced respiratory disease and AFM in a mouse model of infection, to test the hypothesis that antibodies efficiently preclude EV- D68 from causing AFM by preventing dissemination to the CNS; and 2) investigate factors that determine the efficacy of antibody at inhibiting EV-D68 infection in differentiated primary human airway epithelial cells at an air-liquid interface, to test the hypothesis that antibodies poorly protect against initial respiratory mucosal infection. Overall, these studies will help determine whether EV-D68 neutralizing antibodies are a mechanistic correlate of protection from AFM by pinpointing the quantity and quality of antibodies capable of restricting EV- D68 infection to the respiratory tract. Industry collaborators are developing protective mAbs made by the PI as human therapeutic agents, which would be the only available targeted therapy for children with EV-D68 infection. Thus, these studies directly translate to importance in human health in addition to contributing to a more fundamental understanding of disease.

项目总结/摘要 急性弛缓性肌萎缩症（AFM）是2014年在美国出现的儿童脊髓灰质炎样疾病。 从那时起，AFM每隔一年的8月至10月爆发一次，与肠道病毒的爆发同时发生 D 68（EV-D 68）感染。越来越多的证据表明，EV-D 68是AFM的主要原因。EV-D68， 与脊髓灰质炎病毒属于同一肠道病毒属，主要引起呼吸道感染。但 EV-D 68的神经发病机制和人体免疫应答的特点 我们对此知之甚少。这个为期五年的研究职业发展奖将提供培训， 发展PI建立独立研究计划所需的技能，重点是 了解EV-D 68如何导致呼吸系统和神经系统疾病以及人类抗体如何改变这种疾病 发病机制目前，PI是儿科传染病终身教职的助理教授 以及北卡罗来纳州大学查佩尔山医学院的微生物学和免疫学。他 迄今为止的培训主要集中在人单克隆抗体（mAb）的分离和表征， 既往EV-D 68感染的受试者。他将通过进一步的培训来补充这一经验， EV-D 68感染的体内小鼠和离体人体组织模型，用于研究其发病机制 病毒和人类抗体，无论是单克隆和多克隆，如何修改发病机制。的短期目标 拟议的研究是为了验证人类抗体阻止EV-D 68引起的核心假设， AFM，但不能预防呼吸道疾病。PI将由国家专家指导， 小核糖核酸病毒（克雷格卡梅隆和斯坦利柠檬博士），人气道上皮培养物（雷蒙德博士 Pickles）、病毒感染的小鼠模型（Mark海瑟博士）和人抗体（James Crowe，Jr.博士）。的 具体目的是1）确定EV-D 68特异性人抗体如何修饰病毒诱导的呼吸道感染， 疾病和小鼠感染模型中的原子力显微镜，以测试抗体有效阻止EV-的假设 D 68通过防止传播到CNS而引起AFM;和2）研究决定AFM的因素。 抗体抑制EV-D 68感染分化的原代人气道上皮细胞的功效 空气-液体界面，以检验抗体对初始呼吸道粘膜保护作用差的假设 感染总的来说，这些研究将有助于确定EV-D 68中和抗体是否是一种机制， 通过精确定位能够限制EV的抗体的数量和质量， D 68呼吸道感染。行业合作者正在开发PI生产的保护性mAb， 人类治疗剂，这将是EV-D 68儿童唯一可用的靶向治疗 感染因此，这些研究除了有助于人类健康之外，还直接转化为对人类健康的重要性。 对疾病有更基本的了解。

项目成果

A counterintuitive antibody cocktail disrupts coxsackievirus.

• DOI: 10.1016/j.chom.2022.08.010
• 发表时间: 2022-09-14
• 期刊: CELL HOST & MICROBE
• 影响因子: 30.3
• 作者: Zost, Seth J.;Vogt, Matthew R.
• 通讯作者: Vogt, Matthew R.

An unexpected, pH-sensitive step of the enterovirus D68 lifecycle.

• DOI: 10.1128/mbio.02281-23
• 发表时间: 2023-12-19
• 期刊: mBio
• 影响因子: 6.4

Enterovirus D68: a test case for the use of immunological surveillance to develop tools to mitigate the pandemic potential of emerging pathogens.

• DOI: 10.1016/s2666-5247(21)00312-8
• 发表时间: 2022-03
• 期刊: The Lancet. Microbe
• 作者: Nguyen-Tran H;Park SW;Messacar K;Dominguez SR;Vogt MR;Permar S;Permaul P;Hernandez M;Douek DC;McDermott AB;Metcalf CJE;Grenfell B;Spaulding AB
• 通讯作者: Spaulding AB