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The effect of pandemic influenza H1N1 viral infection on house dust mite sensitized mice

University of British Columbia

A disproportionately large number of asthmatics experienced morbidity and mortality during the 2009 H1N1 pandemic. To date, there is little information on the mechanisms behind this epidemiological and clinical observation. Using a murine asthma model, we sought to determine the effects of airway inflammation on host responses to pandemic H1N1 (pH1N1) infection. We hypothesized that mice with an allergic airway phenotype would have a greater viral susceptibility to pH1N1 infection and a dysregulated host response that prevents effective viral clearance and leads to increased burden of pulmonary inflammation, resulting in poor clinical outcomes. We established a murine allergic airway model using house dust mite (HDM) extract. We intranasally instilled male BALB/c mice with HDM or sham PBS daily for two weeks; after which we introduced a single intranasal dose of pH1N1 virus or control vehicle fluid (CAF). HDM or PBS instillation continued daily post-viral infection (pi) forming four groups: 1) sham-sensitized + CAF, 2) HDM-sensitized + CAF, 3) sham-sensitized + pH1N1, and 4) HDM-sensitized + pH1N1. Mice were weighed daily. Virus-infected animals were euthanized at 1-hr pi and on Day 1, 2, 4, 5, 6, and 8 pi and non-infected animals were euthanized on Day 0 and 8 pi. Viral titre, interferon-β (IFN β), and interferon-stimulated gene (ISG) expression patterns were determined by qPCR on RNA extracted from homogenized lung tissue. IFN β protein levels were evaluated by ELISA in bronchoalveolar lavage. Pulmonary inflammation was quantified using H&E stain on formalin-fixed paraffin-embedded lung tissue. HDM-sensitized animals exhibited significantly greater weight loss than sham-sensitized animals following infection. Also, HDM-sensitized mice had significantly higher viral titres on Day 8 pi as compared to sham-sensitized mice. Downstream ISG inductions were dampened in HDM-sensitized, virus-infected animals despite comparable initial IFN β response in HDM- and sham-sensitized mice. We also observed mixed-type pulmonary inflammation in HDM-sensitized mice following pH1N1 infection. Our data suggest dysregulated host ISG responses, combined with the overwhelming burden of pulmonary inflammation, contribute to impaired viral clearance and weight loss indicative of detrimental health outcomes in animals sensitized with HDM following pH1N1 infection.

Text

2016-07-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58438

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/