title: Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters.
abstract: Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem-mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO2challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination.
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Zukor
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Hurst
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Siddharthan
authors.affiliation: Utah Veterinary Diagnostics Laboratory, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Van Wettere
authors.affiliation: The Heart Research Institute and Department of Physiology, University of Sydney, Sydney, NSW, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Pilowsky
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA. john.morrey@usu.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D001933:Brain Stem / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002452:Cell Count; D003412:Cricetulus; D004576:Electromyography / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D009046:Motor Neurons / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009431:Neural Conduction; D020556:Neutrophil Infiltration; D010791:Phrenic Nerve / Q000276:immunology* / Q000473:pathology / Q000821:virology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014902:West Nile virus / Q000472:pathogenicity / Q000502:physiology
keywords: Breathing; Electrophysiology; Phrenic; Respiratory; Sequelae; West Nile virus