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Lethal Avian Influenza A (H5N1) Virus Induces Ataxic Breathing with Reduced Neurokinin 1 Receptor Expression in the Pre‐Botzinger Complex in Mice
Author(s) -
Zhuang Jianguo,
Zang Na,
Ye Chunyan,
Xu Fadi
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1055.8
Subject(s) - hypoxemia , biology , virus , tachypnea , immunology , virology , medicine , tachycardia
The most common symptoms prior to death in patients infected by lethal influenza A (H5N1) are shortness of breath (tachypnea) and respiratory failure. Although the death has been observed in mice at 7 day postinfection, dynamic process of the ventilatory disorders leading to respiratory failure over the infection period and the underlying mechanisms has not been investigated. To this end, the mice were intranasally inoculated with vehicle (Ctrl), 100 PFU HK483 (lethal strain) or HK486 virus (nonlethal strain). We first measured ventilation and arterial blood pH and gases at 0 (before), 2, 4, and 6 days postinfection (dpi). Ctrl and HK486 mice showed no change over the infection period, while HK483 mice presented: 1) gradual body weight loss and hypothermia; 2) a remarkable tachypnea at 2–4 dpi and an ataxic breathing with appearance of long‐lasting apneas at 6 dpi; and 3) hypoxemia and hypercapnemia after 4 dpi that were worse at 6 dpi. Because lethal H5N1 virus is neurotropic and ataxic breathing (hypoxemia) has been reported in rats with an insufficient expression of neural neurokinin 1 receptor (NK1R) in the Pre‐Botzinger complex (PBC), we second asked if HK483 virus replicated in the PBC to induce apoptosis and reduce the population of neurons expressing NK1R. After euthanasia and fixation at 6 dpi, the medullary sections were processed to detect the nucleoprotein of H5N1 virus (NP) alone or coupled with immunoreactivity (IR) of NK1R or CASP3 (a marker for apoptosis). The results showed that HK483 but not HK486 replicated in PBC neurons, particularly local NK1R neurons and reduced the population of PBC NK1R neurons by 75%. CASP3‐IR was detectable in the PBC and NK1R neurons solely in HK483 mice. Our results suggest that lethal H5N1 virus replicates in the PBC to induce apoptosis and thereby reduce population of NK1R neurons, contributing to ataxic breathing and respiratory failure. Support or Funding Information Supported by HL‐107462 and HL‐119683