Zukor Katherine, Wang Hong, Hurst Brett L, Siddharthan Venkatraman, Van Wettere Arnaud, Pilowsky Paul M, Morrey John D
Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
Utah Veterinary Diagnostics Laboratory, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT, 84322-5600, USA.
J Neurovirol. 2017 Apr;23(2):186-204. doi: 10.1007/s13365-016-0488-6. Epub 2016 Oct 19.
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 CO challenge. 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.
神经源性呼吸功能障碍是西尼罗河病毒（WNV）疾病的严重后果。需要插管的WNV患者预后较差。我们之前报道过，通过全身体积描记法和膈肌肌电图评估时，感染WNV的啮齿动物似乎也存在呼吸功能障碍。本研究的目的是确定感染WNV的啮齿动物呼吸功能障碍的本质是否为神经源性，以及功能障碍是否是由于脑干呼吸中枢、颈脊髓（CSC）膈运动神经元（PMN）回路紊乱，或两者兼而有之。我们记录了膈神经（PN）活动，发现感染WNV的小鼠中PN振幅降低，证实了呼吸功能障碍的神经学基础。这些结果与CSC运动神经元数量减少有关。然而，我们发现脑干介导的呼吸节律产生或对高碳酸血症的反应没有明显缺陷。PN频率和模式参数正常，并且在CO刺激后所有PN参数都有适当变化。组织学分析显示脑干和CSC中均有广泛的小胶质细胞激活、星形胶质细胞反应性、T细胞和中性粒细胞浸润以及轻度组织病理学损伤，但这些均与PN功能无紧密相关性。在感染WNV的仓鼠中观察到了PN活动、脑干功能、运动神经元数量和组织病理学方面的类似结果，只是组织病理学损伤更严重。综上所述，结果表明急性WNV感染中的呼吸功能障碍主要是由于影响PMN和PN的下运动神经元紊乱，而非脑干紊乱。未来的研究应聚焦于神经元功能障碍、轴突退变和髓鞘形成的标志物。
