Autonomic Nervous Dysfunction in Hamsters Infected with West Nile Virus

Abstract

Clinical studies and case reports clearly document that West Nile virus (WNV) can cause respiratory and gastrointestinal (GI) complications. Other functions controlled by the autonomic nervous system may also be directly affected by WNV, such as bladder and cardiac functions. To investigate how WNV can cause autonomic dysfunctions, we focused on the cardiac and GI dysfunctions of rodents infected with WNV. Infected hamsters had distension of the stomach and intestines at day 9 after viral challenge. GI motility was detected by a dye retention assay; phenol red dye was retained more in the stomachs of infected hamsters as compared to sham-infected hamsters. The amplitudes of electromygraphs (EMGs) of intestinal muscles were significantly reduced. Myenteric neurons that innervate the intestines, in addition to neurons in the brain stem, were identified to be infected with WNV. These data suggest that infected neurons controlling autonomic function were the cause of GI dysfunction in WNV-infected hamsters. Using radiotelemetry to record electrocardiograms and to measure heart rate variability (HRV), a well-accepted readout for autonomic function, we determined that HRV and autonomic function were suppressed in WNV-infected hamsters. Cardiac histopathology was observed at day 9 only in the right atrium, which was coincident with WNV staining. A subset of WNV infected cells was identified among cells with hyperplarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) as a marker for cells in the sinoatrial (SA) and atrioventricular (AV) nodes. The unique contribution of this study is the discovery that WNV infection of hamsters can lead to autonomic dysfunction as determined by reduced HRV and reduced EMG amplitudes of the GI tract. These data may model autonomic dysfunction of the human West Nile neurological disease.

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…Additional studies using electromyography in WNV-inoculated hamsters have also provided correlations between autonomic dysfunction related to respiratory distress [112] and gastrointestinal [185] symptoms following WNV infection related to peripheral neuronal infection. This model has thus provided much insight not only into neuroinvasive mechanisms of flaviviruses but also into subsequent pathological manifestations that can be attributed to motor neuron infection, death and viral persistence.…”

Autonomic and peripheral nervous system function in acute tick‐borne encephalitis

“…described autonomic symptoms, for example, distension of stomach and intestines and a reduction in the HRV, in an experimental model of hamsters infected with West Nile virus (Wang et al. 2011). Histopathological analysis in this model revealed that neuronal structures relevant for the ANS, that is, neurons in the brain stem, myenteric neurons, and cells in the sinoatrial and atrioventricular nodes were infected with West Nile virus.…”

Comparative Pathology of Neurovirulent Lineage 1 (NY99/385) and Lineage 2 (SPU93/01) West Nile Virus Infections in BALBc Mice

“…Recent studies 27,46 seeking to find neurological explanations for the respiratory, gastrointestinal, bladder, and cardiac dysfunction found in some humans with WNV infection used WNV-infected hamsters, which, like mice, 21 show gastric and intestinal distension. They found by electromyograph (EMG) electrophysiological suppression of the diaphragm either directly due to WNV-infected neurons found by immunostaining in the brainstem and mid-cervical spinal cord or indirectly via altered vagal afferent function.…”