Abstract
H5N1 virus infection results in ~60% mortality in patients primarily due to respiratory failure, but the underlying causes of mortality are unclear. The goal of this study is to reveal respiratory disorders occurring at the early stage of infection that may be responsible for subsequent respiratory failure and death. BALB/c mice were intranasally infected with one of two H5N1 virus strains: HK483 (lethal) or HK486 (non-lethal) virus. Pulmonary ventilation and the responses to hypoxia (HVR; 7% O2 for 3 min) and hypercapnia (HCVR; 7% CO2 for 5 min) were measured daily at 2 days prior and 1, 2, and 3 days postinfection (dpi) and compared to mortality typically by 8 dpi. At 1, 2, and 3 dpi, immunoreactivities (IR) of substance P (SP-IR) in the nodose ganglion or tyrosine hydroxylase (TH-IR) in the carotid body coupled with the nucleoprotein of influenza A (NP-IR) was examined in some mice, while arterial blood was collected in others. Our results showed that at 2 and 3 dpi: 1) both viral infections failed to alter body temperature and weight, , or induce viremia while producing similarly high lung viral titers; 2) HK483, but not HK486, virus induced tachypnea and depressed HVR and HCVR without changes in arterial blood pH and gases; and 3) only HK483 virus led to NP-IR in vagal SP-IR neurons, but not in the carotid body, and increased density of vagal SP-IR neurons. In addition, all HK483, rather than HK486, mice died at 6 to 8 dpi and the earlier death was correlated with more severe depression of HVR and HCVR. Our data suggest that tachypnea and depressed HVR/HCVR occur at the early stage of lethal H5N1 viral infection associated with viral replication and increased SP-IR density in vagal neurons, which may contribute to the respiratory failure and death.
Highlights
Patients infected by highly pathogenic avian influenza (HPAI) H5N1 viruses have a spectrum of clinical abnormalities, ranging from mild symptoms to respiratory failure and death [1,2]
We examined eupneic breathing and respiratory intervals (RR) variation at -2 to 3 dpi among the mice inoculated with vehicle (Ctrl), Hong Kong/483/97 (HK483) or Hong Kong/486/97 (HK486) virus
The eupneic breathing and RR in HK486 mice were similar to those observed in Ctrl mice at -2 to 3 dpi and no changes were found in these variables until 2 dpi in HK483 mice (Figs 2 and 3)
Summary
Patients infected by highly pathogenic avian influenza (HPAI) H5N1 viruses have a spectrum of clinical abnormalities, ranging from mild symptoms to respiratory failure and death [1,2]. The current unavailability of effective vaccine coupled with the continuous zoonotic transmission of endemic H5N1 viruses in domesticated birds makes widespread epidemics highly plausible, if viral mutations lead to more sustainable human-to-human transmission. Both determinations of the lethality of the infection at the early stage and development of corresponding effective treatments to prevent the subsequent respiratory failure are urgently needed. We hypothesized that depressed HVR and HCVR would occur in the early stage of lethal H5N1 viral infection and could be correlated with the death
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