Lethal Avian Influenza A (H5N1) Virus Replicates in Pontomedullary Chemosensitive Neurons and Depresses Hypercapnic Ventilatory Response in Mice

Jianguo Zhuang, Na Zang, Chunyan Ye, Fadi Xu
American Journal of Physiology. Lung Cellular and Molecular Physiology 2019 January 10
The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days post-infection (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 if the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or 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 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.

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