Abstract
BackgroundCellular bioenergetics (cellular respiration and accompanying ATP synthesis) is a highly sensitive biomarker of tissue injury and may be altered following infection. The status of cellular mitochondrial O2 consumption of the lung in pulmonary RSV infection is unknown.MethodsIn this study, lung fragments from RSV-infected BALB/c mice were evaluated for cellular O2 consumption, ATP content and caspase activity. The disease was induced by intranasal inoculation with the RSV strain A2 and lung specimens were analyzed on days 2–15 after inoculation. A phosphorescence O2 analyzer that measured dissolved O2 concentration as a function of time was used to monitor respiration. The caspase-3 substrate analogue N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin (Ac-DEVD-AMC) was used to monitor intracellular caspases.ResultsO2 concentration declined linearly with time when measured in a sealed vial containing lung fragment and glucose as a respiratory substrate, revealing its zero-order kinetics. O2 consumption was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Cellular respiration increased by 1.6-fold (p<0.010) and ATP content increased by 3-fold in the first week of RSV infection. Both parameters returned to levels found in uninfected lungs in the second week of RSV infection. Intracellular caspase activity in infected lungs was similar to uninfected lungs throughout the course of disease.ConclusionsLung tissue bioenergetics is transiently enhanced in RSV infection. This energy burst, triggered by the virus or virus-induced inflammation, is an early biomarker of the disease and may be targeted for therapy.
Highlights
Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia worldwide, infecting most children by 2 years of age [1]
HEp-2 and Vero cells were obtained from American Type Culture Collection (ATCC; Manassas, VA)
The rate of respiration (k, the negative of the slope of [O2] vs. t) was 1.4 μM O2 min-1. This rate decreased to 0.3 μM O2 min-1 (78% inhibition) after the addition of 10 mM sodium cyanide, confirming the oxidation occurred mainly in the mitochondrial respiratory chain
Summary
Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia worldwide, infecting most children by 2 years of age [1]. Severe disease occurs in premature infants and individuals with compromised respiratory, cardiac or immune system [2,3]. The primary immune response is not efficient against the initial infection, but results in an effective memory response against reinfection. The virus generates CD4 and CD8 T cell responses that result in classical interferon-gamma production. Both the humoral and cellmediated immune responses play roles in virus clearance, and contribute to the immunopathology of the respiratory tract. The status of cellular mitochondrial O2 consumption of the lung in pulmonary RSV infection is unknown
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