CHARACTERIZATION OF ASTROVIRUS VA1, A NOVEL NEUROTROPIC VIRUS

新型神经营养病毒 ASTROVIRUS VA1 的特征

• 批准号: 10331766
• 负责人: Andrew Bok Seng Janowski
• 金额: $ 16.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331766
• 关键词: Accounting; Acute; Address; Adult; Advisory Committees; Affect; Animals; Antibodies; Antiviral Therapy; Astrocytes; Astrovirus; Award; Biological Assay; Biology; CRISPR/Cas technology; Caco-2 Cells; Cattle; Cell Culture System; Cell Culture Techniques; Cell Line; Cell Lineage; Cells; Cellular Tropism; Central Nervous System Diseases; Central Nervous System Infections; Cerebrospinal Fluid; Chickens; Child; Clinical; Data; Development; Development Plans; Diagnostic; Diamond; Disease; Doctor of Philosophy; Encephalitis; Enrollment; Epidemiology; Etiology; Experimental Designs; Experimental Models; Exposure to; Family; Family suidae; Foundations; Future; Genes; Goals; Growth; Human; Immune; Immune response; Immunohistochemistry; In Situ Hybridization; In Vitro; Infection; Institution; Integration Host Factors; Interferon Type I; Interferon-beta; Interferons; K-Series Research Career Programs; Kinetics; Master' s Degree; Measures; Mediating; Mentors; Mink; Modeling; Names; Neuraxis; Neuroglia; Neurologic Deficit; Neurons; Neurotropism; Outcome; Patients; Pattern; Pattern recognition receptor; Physicians; Pleocytosis; Prevalence; Proteins; Publishing; Quantitative Reverse Transcriptase PCR; RNA; RNA Phages; Receptor Signaling; Reporting; Research; Research Project Grants; Retrospective cohort; Role; Sampling; Scientist; Seroprevalences; Specimen; Supporting Cell; Surveys; System; Technology; Training; Universities; Vertebrates; Viral; Virus; Washington; Work; base; brain tissue; burden of illness; career; career development; clinical investigation; cohort; design; emerging pathogen; exposed human population; gastrointestinal infection; improved; improved outcome; in vitro Model; in vivo; indexing; insight; loss of function; metagenomic sequencing; nervous system disorder; neurotropic; neurotropic virus; neutralizing antibody; next generation sequencing; novel; novel virus; pathogen; prospective; receptor; repository; research clinical testing; response; skills; targeted treatment; translational medicine; virus host interaction

Project Summary/Abstract This mentored career development award (K08) proposal describes the research and educational plans for the candidate, Andrew Janowski MD. His long-term goal is to discover and characterize viral causes of central nervous system (CNS) infection. One entity, encephalitis, is often caused by infectious pathogens, but frequently an etiology cannot be identified despite extensive clinical testing. A subset of encephalitis cases are anticipated to be caused by novel viruses or viruses with an unappreciated neurotropism. Dr. Janowski has previously used next-generation sequencing technology to discover a novel family of viruses named statoviruses and has also increased the number of known RNA bacteriophages by over six-fold. He will apply these skills to identify novel pathogens in CNS infections and to characterize their biology. Astrovirus VA1 (VA1), a virus originally discovered by Dr. Janowski's mentor, David Wang PhD, has been identified as an emerging cause of encephalitis. However, studies of the fundamental biology of this virus has been precluded by the lack of an experimental model of infection. Dr. Janowski has developed the first cell culture model of VA1 infection in vitro, and now the biology of VA1 infection can be elucidated using this system. In Aim 1, he will develop an in vitro model of VA1 CNS infection. He will define host expression profiles upon infection and determine if there are any VA1 strain specific cellular tropisms. The host immune response to VA1 infection is also poorly defined, but preliminary evidence suggests that interferon-β is induced by VA1 and addition of exogenous interferon reduces VA1 replication. For Aim 2, Dr. Janowski will use a CRISPR/Cas- 9 approach to define pattern recognition receptors and interferon stimulated genes that mediate the interferon response. In Aim 3, Dr. Janowski will use a neutralization assay to define the seroprevalence of neutralizing antibodies to VA1. He will also use a qRT-PCR assay to define the burden of CNS diseases caused by VA1, as he has a repository of clinical specimens from patients with acute CNS diseases. Characterizing VA1 will prepare Dr. Janowski to transition as an independent physician-scientist by the end of the K08 award period. His career development will be overseen by his co-mentors, Drs. David Wang and Gregory Storch, with Drs. Robyn Klein, Herbert “Skip” Virgin, Mike Diamond, and David Hunstad forming an illustrious advisory committee that will assist in career development and experimental design. In addition, Dr. Janowski will complete a master's degree in clinical investigation in translational medicine at Washington University in St Louis to enhance his formal scientific training. He has the support of a world-class institution, an outstanding group of mentors and advisors, a well-developed educational plan, and a research project that will provide unique and provocative results regarding the biology of VA1. The results of this K08 proposal will not only build upon host-virus interactions in CNS infections but it will launch the independent research career of Dr. Janowski.

项目摘要/摘要 这个修订的职业发展奖（K08）提案描述了研究和教育计划 对于候选人，安德鲁·扬斯基（Andrew Janowski）医学博士。他的长期目标是发现并表征 中枢神经系统（CNS）感染。一个实体，脑炎，通常是由感染性病原体引起的，但 通常，病因不能识别为所需的广泛临床测试。脑炎病例的一部分是 预计将由新的病毒或病毒引起，具有未引起的神经性神经性。 Janowski博士有 以前使用下一代测序技术发现了一种新型病毒家族 Statoviruses，还将已知RNA细菌的数量增加了六倍以上。他将申请 这些技能以鉴定中枢神经系统感染中的新病原体并表征其生物学。 Astrovirus VA1（VA1）是一种由Janowski博士的心理David Wang PhD发现的病毒 被确定为脑炎的新兴原因。但是，研究该病毒的基本生物学 缺乏感染的实验模型，已经排除了。 Janowski博士开发了第一个牢房 VA1感染的培养模型在体外，现在可以阐明VA1感染的生物学 系统。在AIM 1中，他将开发VA1 CNS感染的体外模型。他将定义主机表达概况 感染后，确定是否存在任何VA1菌株特异性细胞向性毒性。宿主免疫反应 VA1感染的定义也很差，但是初步证据表明，干扰素β是由VA1诱导的 外源干扰素的添加减少了VA1复制。对于AIM 2，Janowski博士将使用CRISPR/CAS- 9定义模式识别受体和干扰刺激基因的方法介导了干扰 回复。在AIM 3中，Janowski博士将使用紧张的测定法来定义中和 VA1的抗体。他还将使用QRT-PCR测定法来定义由VA1引起的中枢神经系统疾病的伯恩。 由于他有来自急性中枢神经系统疾病患者的临床标本的存储库。 表征VA1的表征将使Janowski博士成为一个独立的物理科学家的过渡 K08奖励期结束。他的职业发展将由他的联合主管博士监督。大卫·王（David Wang） 和格雷戈里·斯托奇（Gregory Storch），博士。 Robyn Klein，Herbert“ Skip” Virgin，Mike Diamond和David Hunstad成立 一个杰出的咨询委员会，将有助于职业发展和实验设计。此外， Janowski博士将完成华盛顿转化医学临床调查硕士学位 圣路易斯大学以增强他的正式科学培训。他得到了世界一流机构的支持， 一群杰出的导师和顾问，一个完善的教育计划，以及一个研究项目 将为VA1的生物学提供独特而挑衅的结果。该K08提案的结果将 不仅基于中枢神经系统感染中的宿主病毒互动，而且还将启动独立研究生涯 Janowski博士。

项目成果

Infection and Propagation of Astrovirus VA1 in Cell Culture.

• DOI: 10.1002/cpmc.73
• 发表时间: 2019-02-01
• 期刊: Current protocols in microbiology
• 作者: Janowski, Andrew B;Wang, David
• 通讯作者: Wang, David

Seroprevalence of SARS-CoV-2 Antibodies in Children and Adults in St. Louis, Missouri, USA.

• DOI: 10.1128/msphere.01207-20
• 发表时间: 2021-02-03
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Smith BK;Janowski AB;Danis JE;Harvey IB;Zhao H;Dai YN;Farnsworth CW;Gronowski AM;Roper S;Fremont DH;Wang D
• 通讯作者: Wang D

Perceptions of risk of SARS-CoV-2 transmission in social and educational activities by infectious diseases and general pediatric healthcare providers, a pre-vaccine risk perception cross-sectional survey.

• DOI: 10.1371/journal.pone.0263767
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Janowski AB;Polgreen PM;Beekmann SE;Newland JG
• 通讯作者: Newland JG

Beyond the Gastrointestinal Tract: The Emerging and Diverse Tissue Tropisms of Astroviruses.

• DOI: 10.3390/v13050732
• 发表时间: 2021-04-22
• 期刊: Viruses
• 作者: Janowski AB

High Seropositivity Rate of Neutralizing Antibodies to Astrovirus VA1 in Human Populations.

• DOI: 10.1128/msphere.00484-21
• 发表时间: 2021-10-27
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Janowski AB;Owen MC;Dudley H;López T;Espinosa R;Elvin-Lewis M;Colichon A;Arias CF;Burbelo PD;Wang D
• 通讯作者: Wang D