PDF(Pubmed)
Abstract：
Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory and neurologic disease [acute flaccid myelitis (AFM)]. Intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with US/IL/14-18952 (IL52), a clinical isolate from the 2014 EV-D68 epidemic, results in many of the pathogenic features of human AFM, including viral infection of the spinal cord, death of motor neurons, and resultant progressive paralysis. In distinction, CA/14-4231 (CA4231), another clinical isolate from the 2014 EV-D68 outbreak, does not cause paralysis in mice, does not grow in the spinal cord, and does not cause motor neuron loss following IM injection. A panel of chimeric viruses containing sequences from IL52 and CA4231 was used to demonstrate that VP1 is the main determinant of EV-D68 neurovirulence following IM injection of neonatal SW mice. VP1 contains four amino acid differences between IL52 and CA4231. Mutations resulting in substituting these four amino acids (CA4231 residues into the IL52 polyprotein) completely abolished neurovirulence. Conversely, mutations resulting in substituting VP1 IL52 amino acid residues into the CA4231 polyprotein created a virus that induced paralysis to the same degree as IL52. Neurovirulence following infection of neonatal SW mice with parental and chimeric viruses was associated with viral growth in the spinal cord.
OBJECTIVE: Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.
OBJECTIVE: Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.
摘要：
肠道病毒D68（EV-D68）是一种新兴的病原体，可引起严重的呼吸道和神经系统疾病[急性弛缓性脊髓炎（AFM）]。用US/IL/14-18952（IL52）肌内（IM）注射新生SwissWebster（SW）小鼠，2014年EV-D68流行的临床分离株，导致人类AFM的许多致病特征，包括脊髓的病毒感染，运动神经元死亡，并导致进行性瘫痪。在区别上,CA/14-4231(CA4231),2014年EV-D68爆发的另一种临床分离株，不会导致老鼠瘫痪，不会在脊髓中生长，并且在IM注射后不会导致运动神经元丢失。一组含有来自IL52和CA4231的序列的嵌合病毒用于证明VP1是IM注射新生SW小鼠后EV-D68神经毒力的主要决定因素。VP1含有IL52和CA4231之间的四个氨基酸差别。导致取代这四个氨基酸(CA4231残基进入IL52多蛋白)的突变完全消除了神经毒力。相反，导致将VP1IL52氨基酸残基替换为CA4231多蛋白的突变产生了一种与IL52相同程度的诱导瘫痪的病毒。用亲本和嵌合病毒感染新生SW小鼠后的神经毒力与脊髓中的病毒生长有关。
目的：新兴病毒允许我们研究导致疾病严重程度增加的突变。肠道病毒D68(EV-D68),曾经是罕见呼吸道疾病的原因，最近获得了引起严重呼吸道和神经系统疾病的能力。嵌合病毒用于证明病毒结构蛋白VP1决定脊髓的生长，运动神经元丢失，用EV-D68肌内（IM）注射新生SwissWebster（SW）小鼠后的瘫痪。这些结果对于预测未来EV-D68流行病的临床结果以及靶向逆行运输作为治疗病毒诱导的神经系统疾病的潜在策略具有相关性。
目的：新兴病毒允许我们研究导致疾病严重程度增加的突变。肠道病毒D68(EV-D68),曾经是罕见呼吸道疾病的原因，最近获得了引起严重呼吸道和神经系统疾病的能力。嵌合病毒用于证明病毒结构蛋白VP1决定脊髓的生长，运动神经元丢失，用EV-D68肌内（IM）注射新生SwissWebster（SW）小鼠后的瘫痪。这些结果对于预测未来EV-D68流行病的临床结果以及靶向逆行运输作为治疗病毒诱导的神经系统疾病的潜在策略具有相关性。
