Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice.
Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice.
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DOI：
10.1152/ajplung.00324.2018
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Jianguo Zhuang;N. Zang;Chunyan Ye;Fadi Xu
中科院分区：
文献类型：
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作者：
Jianguo Zhuang;N. Zang;Chunyan Ye;Fadi Xu
高致病性H5 N1（HK 483）病毒感染小鼠后2天（dpi）高碳酸血症性反应（dHCVR，20%↓）降低，7天死亡，但相关机制尚不完全清楚。颈动脉体中的血管球细胞和蓝斑（LC）中的儿茶酚胺能神经元、后斜方核（RTN）中的神经激肽1受体（NK 1 R）表达神经元和中缝核中的多巴胺能神经元是化学敏感的并且负责HCVR。我们询问dHCVR是否在感染期间随着病毒在这些细胞/神经元中的复制而变得更糟。鼻内接种生理盐水或HK 483病毒的小鼠在0、2、4或6 dpi暴露于高碳酸血症5 min，然后通过免疫组织化学测定单独的H5 N1甲型流感病毒（NP）的核蛋白表达以及与1）颈动脉体和LC中的酪氨酸羟化酶（TH）、2）RTN中的NK 1 R和3）中缝中的色氨酸羟化酶（TPH）偶联的核蛋白表达。HK 483病毒感染使HCVR在2、4和6 dpi时减弱20%、50%和65%。在4和6 dpi时，在脑桥延髓神经元相关核团（但不在颈动脉体）中观察到NP，尤其是在20%的RTN NK 1 R，35%的LC TH和约10%的中缝TPH神经元中。感染显着降低局部NK 1 R或TPH的免疫反应性和神经元表达NK 1 R或TPH的人口。我们得出的结论是，HK 483病毒感染了脑桥延髓呼吸核，特别是RTN、LC和中缝中的化学敏感神经元，导致6 dpi时HCVR严重抑制和呼吸衰竭。H5 N1病毒感染是致命的，由于呼吸衰竭，但相关的机制仍不清楚。在这项研究中，我们证明了在一定程度上逐渐减少高碳酸血症的反应，导致呼吸衰竭超过6天的感染。死亡与脑桥延髓神经元相关核团，特别是中央化学敏感神经元中的病毒复制有关。这些结果不仅提供了对H5 N1病毒感染致死机制的深入了解，而且还为开发相应治疗方法以最大限度地减少和预防呼吸衰竭提供了线索。
The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by ∼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and ∼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi. NEW & NOTEWORTHY The H5N1 virus infection is lethal due to respiratory failure, but the relevant mechanisms remain unclear. In this study, we demonstrated a gradual diminution of hypercapnic ventilatory response to a degree, leading to respiratory failure over a 6-day infection. Death was associated with viral replication in the pontomedullary respiratory-related nuclei, especially the central chemosensitive neurons. These results not only provide insight into the mechanisms of the lethality of H5N1 viral infection but also offer clues in the development of corresponding treatments to minimize and prevent respiratory failure.