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A mouse model of paralytic myelitis caused by enterovirus D68

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  • A mouse model of paralytic myelitis caused by enterovirus D68

    Source: http://journals.plos.org/plospathoge...l.ppat.1006199
    A mouse model of paralytic myelitis caused by enterovirus D68

    • Alison M. Hixon,
    • Guixia Yu,
    • J. Smith Leser,
    • Shigeo Yagi,
    • Penny Clarke,
    • Charles Y. Chiu,
    • Kenneth L. Tyler

    Abstract

    In 2014, the United States experienced an epidemic of acute flaccid myelitis (AFM) cases in children coincident with a nationwide outbreak of enterovirus D68 (EV-D68) respiratory disease. Up to half of the 2014 AFM patients had EV-D68 RNA detected by RT-PCR in their respiratory secretions, although EV-D68 was only detected in cerebrospinal fluid (CSF) from one 2014 AFM patient. Given previously described molecular and epidemiologic associations between EV-D68 and AFM, we sought to develop an animal model by screening seven EV-D68 strains for the ability to induce neurological disease in neonatal mice. We found that four EV-D68 strains from the 2014 outbreak (out of five tested) produced a paralytic disease in mice resembling human AFM. The remaining 2014 strain, as well as 1962 prototype EV-D68 strains Fermon and Rhyne, did not produce, or rarely produced, paralysis in mice. In-depth examination of the paralysis caused by a representative 2014 strain, MO/14-18947, revealed infectious virus, virion particles, and viral genome in the spinal cords of paralyzed mice. Paralysis was elicited in mice following intramuscular, intracerebral, intraperitoneal, and intranasal infection, in descending frequency, and was associated with infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs. Virus isolated from spinal cords of infected mice transmitted disease when injected into na?ve mice, fulfilling Koch?s postulates in this model. Finally, we found that EV-D68 immune sera, but not normal mouse sera, protected mice from development of paralysis and death when administered prior to viral challenge. These studies establish an experimental model to study EV-D68-induced myelitis and to better understand disease pathogenesis and develop potential therapies.
    Author summary

    Reports of polio-like paralysis, referred to as acute flaccid myelitis (AFM), have recently emerged in association with infections caused by enterovirus D68 (EV-D68). In the second half of 2014, 120 cases of AFM, mostly in young children, were reported during a nationwide outbreak of EV-D68 respiratory disease. The number of AFM cases has risen again in 2016. Although epidemiological evidence between EV-D68 infection and AFM is accumulating, a causal link has not been definitely established. Here we demonstrate that strains of EV-D68 recovered during the 2014 epidemic can cause a paralytic illness in mice that resembles human AFM. Evidence that EV-D68 causes paralysis in this mouse model include: (1) loss of spinal cord motor neurons innervating paralyzed limbs, (2) detection of virus in the spinal cord and, specifically, motor neurons, (3) transmission of neurological disease when injecting virus isolated from spinal cords of paralyzed mice into na?ve mice, thus fulfilling Koch?s postulates, and (4) the ability to prevent AFM by pre-administering serum containing EV-D68 antibodies from previously infected mice. This experimental mouse model can be used to better understand the pathogenesis of EV-D68-induced CNS disease and to facilitate the development of potential therapies...


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