Modeling host susceptibility factors in Acute Flaccid Myelitis

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Project Summary/Abstract Modeling host susceptibility factors in Acute Flaccid Myelitis Acute flaccid myelitis (AFM) is a poliomyelitis-like neuroinfectious illness of children whose prevalence has increased dramatically in recent years, occurring in biennial outbreaks in the Unites States since at least 2014. The consequences of AFM are often severe and debilitating lifelong paralysis that may also include respiratory failure. Despite its striking similarity to polio, little is known about disease pathogenesis and few effective treatment options exist. AFM has been connected to neurotropic non-polio enteroviruses, especially Enterovirus D68 (EV68). However, the vast majority of cases of EV68 infections cause mild non-specific viral symptoms or a respiratory syndrome, while only a small minority of patients become paralyzed as a result of spinal motor neuron infection. This observation suggests that the development of AFM requires the intersection of viral infection and host factors that are permissive to neuropathogenesis. We will therefore generate induced pluripotent stem cell (iPS) lines from tissues previously donated by AFM patients, and use these to model AFM resulting from EV68 infection in vitro. The initial experiments within the scope of this application will focus on spinal motor neurons, due to the fact that motor neuron death is the proximate cause of paralysis in AFM patients, and evidence for direct motor neuron infection by EV68. We will characterize the composition and reproducibility of AFM patient derived and control iPS lines differentiated into spinal motor neurons, and determine the baseline susceptibility of the neurons to a variety of cellular stressors. These studies will set the stage for future experiments of EV68 infection of patient-derived iPS motor neurons to better understand host factors that are permissive of viral infection and motor neuron death and dysfunction. The result of this work will be a model system for AFM that faithfully reproduces the affected cell type, in human cells, and on a genetic background with proven susceptibility to disease. The iPS lines will also be capable of modeling other disease-relevant cell types in the future. These cell lines will represent a unique and valuable resource to the AFM research community.