Depressed Hypoxic and Hypercapnic Ventilatory Responses (dHVR and dHCVR) Occur in Mice at the Late Stage of Lethal Avian Influenza A (H5N1) Virus Infection

Abstract

H5N1 viral infection results in ~60% mortality in patients primarily due to respiratory failure, but the relevant mechanisms are unclear. Lethal H5N1 viral infection produced dHVR and dHCVR without significant changes in body weight (BW), body temperature (BT), arterial blood gases, and pulmonary inflammation 2-3 days post-infection in mice (AJRCCM 2013). Here we tested the development of dHVR/dHCVR and disorders of pulmonary functions, leading to respiratory failure at the late stage of infection. The mice were intranasally inoculated with vehicle, 100 PFU HK483 (lethal strain) or HK486 virus (nonlethal strain). At 1 day before or post-inoculation days (PID) 4, 5, 6 and 7, VE, HVR (7% O2 for 3 min) and HCVR (7% CO2 for 5 min) were measured in awake state followed by collecting arterial blood, BALF, the brain and lung after anesthesia/euthanasia. HK483 and HK486 mice showed a peak viral titer at PID4 that gradually declined thereafter. HVR and HCVR were similar in Ctrl and HK486 mice and were not changed over the infection period. At PID7, HK483 mice were very weak (all died one day later), and exhibited hypoventilation with hypoxemia and hypercapnemia; they also lacked HVR (no response) and HCVR (80%↓) with BW and BT declined by 31% and ~10 ºC, respectively. HK483 but not HK486 significantly decreased lung dry/wet ratio. Total cells in BALF increased in both infected groups, but the increase was more evident in HK483 than HK486 mice. Our data suggest that H5N1 viral infection-induced ventilatory and pulmonary disorders are viral strain-dependent and the gradual deterioration of dHVR and dHCVR may account for the mortality in HK483 mice (Supported by HL119683 and HL107462).