EV-D68-induced CNS disease: pathogenic mechanisms and identification of therapeutic targets.

EV-D68诱导的中枢神经系统疾病：致病机制和治疗靶点的鉴定。

• 批准号: 9436831
• 负责人: Kenneth L. Tyler
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436831
• 关键词: Acute; Acyclovir; Animal Model; Antiviral Agents; Brain; CASP3 gene; Cell Death; Cell Survival; Cells; Central Nervous System Diseases; Central Nervous System Infections; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Cessation of life; Child; Clinical; Data; Development; Disease; Disease Marker; Disease Outbreaks; Disease Progression; Employee Strikes; Encephalitis; Enterovirus; Enterovirus 68; Epidemic; Evaluation; Growth; Herpes encephalitis; Human; Human poliovirus; Immune; Immune response; Immune system; Individual; Infection; Interferons; Intravenous Immunoglobulins; Knowledge; Link; Lung diseases; Meningitis; Modeling; Monitor; Morbidity - disease rate; Motor Neurons; Mus; Myelitis; Neonatal; Nerve Degeneration; Neuraxis; Neurologic; Neuronal Injury; Neuropathogenesis; Paralysed; Pathogenesis; Pathogenicity; Patients; Peripheral; Peripheral Nervous System; Poliomyelitis; Reverse Transcriptase Polymerase Chain Reaction; Site; Slice; Spinal Cord; Spinal Cord Diseases; Spinal cord injury; Testing; Time; Tissues; Tropism; United States; Viral; Virus; Virus Diseases; central nervous system injury; disability; effective therapy; experience; human disease; improved outcome; in vivo Model; mortality; mouse model; nervous system disorder; neuron loss; neurotropic; neurovirulence; new therapeutic target; novel; pathogen; prevent; respiratory; response; therapeutic target; treatment strategy

Virus infections of the central nervous system (CNS) are a significant cause of morbidity and mortality worldwide. Proven treatments are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. Our knowledge of viral CNS infections, particularly those involving the spinal cord, is limited and serves as a barrier against the development of novel treatments for these devastating diseases. Enteroviruses are an important cause of virus-induced CNS infections. Although poliovirus (PV), is perhaps the most well-known of the neurotrophic enteroviruses, several non-polio human EVs also target the CNS and are responsible for numerous clinical manifestations, including encephalitis, myelitis and meningitis. Non-polio EVs are common, causing an estimated 10–15 million or more symptomatic annual infections in the US alone. Though most of these infections do not result in CNS disease data from ourselves and others suggest that these viruses can acquire the ability to be neurovirulent. In recent years large outbreaks of enteroviruses have occurred worldwide and neurotropic enteroviruses have been deemed “re-emerging pathogens”. In 2014, the United States experienced an epidemic of acute flaccid myelitis (AFM) cases in children during a nationwide outbreak of previously rare enterovirus D68 (EV-D68) respiratory disease. Approximately 50% of AFM patients had EV-D68 detected by RT-PCR in respiratory secretions, although EV-D68 was not detected in cerebrospinal fluid from any patient, preventing the establishment of a causative link between EV-D68 and AFM. We have recently shown that clinical isolates of EV-D68 from the 2014 outbreak cause neurologic disease in neonatal mice and propose to use this novel model of virus-induced CNS disease to; (i) increase our understanding of EV-D68-induced CNS disease and investigate how viruses evolve to become neurovirulent (Aim 1); (ii) delineate pathogenic mechanisms that are triggered in the CNS following EV-D68 infection (Aim 3), and (iv) evaluate potential therapeutic targets for EV-D68 induced CNS disease. Our experience with other animal models of virus-induced CNS disease will allow us to rapidly identify whether mechanisms involved in EV-D68 pathogenesis are common to other viruses that infect the CNS and whether treatments which are effective against EV-D68-induced CNS disease have broad spectrum applicability to other virus-induced CNS diseases. Our results are also expected to have relevance non-viral causes of CNS disease, including neurodegeneration

病毒感染的中枢神经系统（CNS）是发病率和死亡率的重要原因