Use of plethysmography in assessing the efficacy of antivirals in a mouse model of pandemic influenza A virus

Abstract

The recently emerged swine-origin H1N1 influenza A virus (IAV) caused a pandemic outbreak in 2009 with higher risk of severe disease among children and pregnant women in their third trimester ( Van Kerkhove et al., 2011), and is continuing to be important seasonal IAV strain. Mice are commonly used in antiviral studies as models of influenza disease, which utilize morbidity and mortality to assess the efficacy of a test compound. Here, we investigated the utility of unrestrained plethysomography to quantify the lung function of IAV-infected BALB/c mice. Administration of a lethal dose (∼30X LD 50) of pandemic H1N1 IAV resulted in a rapid decline in breath volume, as determined by a significant ( P < 0.001) decrease in the pressure associated with inspiration and expiration detected as early as 2 days after virus challenge. Severe disease was also accompanied by a significant ( P < 0.05) increase in breath time on 8 dpi. Plethysmography parameters correlated with weight loss and other parameters of disease such as gross pathology and the weight of the lung. Breath time was reduced in surviving mice challenged with a sublethal dose of virus as compared with normal controls, and is a predictive indicator of outcome in these mice. In antiviral studies, the use of plethysmography resulted in the detection of a clear and rapid treatment response, which was similar to other non-invasive parameters, such as weight change. Oseltamivir and ribavirin significantly ( P < 0.001) improved parameters of lung function, particularly mean breath volume, as early as 2 dpi and in a dose-dependent manner. Moreover, a combination of these two drugs further improved these parameters. Plethysmography provides a sensitive evaluation of lung function in IAV-infected mice in response to antiviral therapy.