Contemporary enterovirus-D68 isolates infect human spinal cord organoids.
Contemporary enterovirus-D68 isolates infect human spinal cord organoids.
复制标题
作者：
肠道病毒D 68（EV-D 68）是一种非脊髓灰质炎肠道病毒，与严重呼吸道疾病和急性弛缓性肌麻痹（AFM）有关，AFM是一种导致儿童瘫痪的脊髓灰质炎样疾病。自2014年以来，AFM的爆发与EV-D 68的流通和遗传多样性增加有关，尽管该病毒是在20世纪60年代发现的。EV-D 68靶向中枢神经系统的机制尚不清楚。由于肠道病毒是人类的病原体，不经常感染其他动物物种，建立人类中枢神经系统模型是了解发病机制的必要条件。在这里，我们描述了两个人类脊髓类器官（hSCO）的模型，EV-D 68感染来自诱导，多能干细胞（iPSC）线。一种hSCO模型主要由脊髓运动神经元组成，而另一种模型包括多个神经元细胞谱系，包括运动神经元、中间神经元和神经胶质细胞。这些hSCO可以用EV-D 68的当代菌株而不是历史菌株有效感染，并且产生细胞外病毒至少2周而没有明显的细胞病变效应。相比之下，感染hSCO与另一种肠道病毒，埃可病毒11，导致显着的结构破坏和细胞凋亡。总之，这些发现表明EV-D 68感染不是AFM患者脊髓中神经元细胞死亡的唯一介质，并且来自免疫应答的继发性损伤可能有助于发病机制。AFM是一种罕见的疾病，会导致受影响儿童的严重发病率，通常会导致终身后遗症。目前尚不清楚EV-D 68如何导致儿童瘫痪，也没有有效的治疗和预防策略。小鼠不是EV-D 68的天然宿主，因此，现有的小鼠模型使用免疫抑制小鼠或新生小鼠、小鼠适应病毒或颅内接种。为了补充现有的模型，我们报告了两个EV-D 68感染的hSCO模型。这些三维多细胞模型由人类细胞组成，包括多种神经谱系，包括运动神经元、中间神经元和神经胶质细胞。这些新的EV-D 68感染的hSCO模型将有助于了解EV-D 68如何损害人类脊髓，这可能会导致这种病毒的新的治疗和预防策略。
Enterovirus D68 (EV-D68) is a nonpolio enterovirus associated with severe respiratory illness and acute flaccid myelitis (AFM), a polio-like illness causing paralysis in children. AFM outbreaks have been associated with increased circulation and genetic diversity of EV-D68 since 2014, although the virus was discovered in the 1960s. The mechanisms by which EV-D68 targets the central nervous system are unknown. Since enteroviruses are human pathogens that do not routinely infect other animal species, establishment of a human model of the central nervous system is essential for understanding pathogenesis. Here, we describe two human spinal cord organoid (hSCO)-based models for EV-D68 infection derived from induced, pluripotent stem cell (iPSC) lines. One hSCO model consists primarily of spinal motor neurons, while the another model comprises multiple neuronal cell lineages, including motor neurons, interneurons, and glial cells. These hSCOs can be productively infected with contemporary strains, but not a historic strain, of EV-D68 and produce extracellular virus for at least 2 weeks without appreciable cytopathic effect. By comparison, infection with hSCO with another enterovirus, echovirus 11, causes significant structural destruction and apoptosis. Together, these findings suggest that EV-D68 infection is not the sole mediator of neuronal cell death in the spinal cord in those with AFM and that secondary injury from the immune response likely contributes to pathogenesis. AFM is a rare condition that causes significant morbidity in affected children, often contributing to life-long sequelae. It is unknown how EV-D68 causes paralysis in children, and effective therapeutic and preventative strategies are not available. Mice are not native hosts for EV-D68, and thus, existing mouse models use immunosuppressed or neonatal mice, mouse-adapted viruses, or intracranial inoculations. To complement existing models, we report two hSCO models for EV-D68 infection. These three-dimensional, multicellular models comprised human cells and include multiple neural lineages, including motor neurons, interneurons, and glial cells. These new hSCO models for EV-D68 infection will contribute to understanding how EV-D68 damages the human spinal cord, which could lead to new therapeutic and prophylactic strategies for this virus.
登录
查看更多内容
影响因子：
13.3
作者：
Jassey, Alagie;Wagner, Michael A.;Galitska, Ganna;Paudel, Bimal;Miller, Katelyn;Jackson, William T.
通讯作者：
Jackson, William T.
影响因子：
46.9
作者：
Maury, Yves;Come, Julien;Nedelec, Stephane
通讯作者：
Nedelec, Stephane
影响因子：
14.8
作者：
Dekkers, Johanna F.;Alieva, Maria;Rios, Anne C.
通讯作者：
Rios, Anne C.
影响因子：
3.7
作者：
Daley, JK;Gechman, LA;Rall, GF
通讯作者：
Rall, GF
影响因子：
5.4
作者：
Belov, GA;Romanova, LI;Agol, VI
通讯作者：
Agol, VI