title: A mouse model of paralytic myelitis caused by enterovirus D68.
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 naïve 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.
authors.affiliation: Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO, United States of America.|Neuroscience Program, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Alison M
authors.identifier: 0000-0002-8373-4311
authors.initials: AM
authors.lastname: Hixon
authors.affiliation: Department of Laboratory Medicine and Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, United States of America.|UCSF-Abbott Viral Diagnostics and Discovery Center, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Guixia
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: J Smith
authors.initials: JS
authors.lastname: Leser
authors.affiliation: California Department of Public Health, Richmond, CA, United States of America.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Penny
authors.identifier: 0000-0001-5540-2910
authors.initials: P
authors.lastname: Clarke
authors.affiliation: Department of Laboratory Medicine and Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, United States of America.|UCSF-Abbott Viral Diagnostics and Discovery Center, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Charles Y
authors.identifier: 0000-0003-2915-2094
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America.|Denver VA Medical Center, Denver, CO, United States of America.|Departments of Immunology and Microbiology, and Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D030016:Enterovirus D, Human; D004769:Enterovirus Infections / Q000150:complications / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009187:Myelitis / Q000473:pathology / Q000821:virology*; D010243:Paralysis / Q000821:virology; D016133:Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology / Q000821:virology