Abstract
BackgroundAsthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor α (IL-4Rα), a critical mediator of Th2 signalling, improved their outcomes.MethodsMale BALB/c mice were intranasally sensitized with house dust mite antigen (Der p 1) for 2 weeks; the mice were then inoculated intranasally with a single dose of pandemic H1N1 (pH1N1). The mice were administered intraperitoneally anti-IL-4Rα through either a prophylactic or a therapeutic treatment strategy.ResultsInfection with pH1N1 of mice sensitized to house dust mite (HDM) led to a 24% loss in weight by day 7 of infection (versus 14% in non-sensitized mice; p < .05). This was accompanied by increased viral load in the airways and a dampened anti-viral host responses to the infection. Treatment of HDM sensitized mice with a monoclonal antibody against IL-4Rα prior to or following pH1N1 infection prevented the excess weight loss, reduced the viral load in the lungs and ameliorated airway eosinophilia and systemic inflammation related to the pH1N1 infection.ConclusionTogether, these data implicate allergic asthma as a significant risk factor for H1N1-related morbidity and reveal a potential therapeutic role for IL-4Rα signalling blockade in reducing the severity of influenza infection in those with allergic airway disease.
Highlights
The 2009 H1N1 influenza A pandemic strain (pH1N1, A(H1N1)pdm09) caused 18,500 deaths, over 12,500 of which were reported in the United States [1, 2]
We found that house dust mite (HDM)-sensitized mice had greater pandemic H1N1 (pH1N1)-related morbidity which was alleviated by interleukin-4 receptor α (IL-4Rα) monoclonal antibody (mAb) blockade
HDM‐sensitized mice experience excessive weight loss following pH1N1 infection To determine how underlying allergic sensitization and airway inflammation impact pH1N1-induced morbidity, mice were intranasally exposed to repeated doses of Phosphate-buffered saline (PBS) or HDM, prior to and following intranasal inoculation with either pH1N1 or Chorioallantoic fluid (CAF)
Summary
The 2009 H1N1 influenza A pandemic strain (pH1N1, A(H1N1)pdm09) caused 18,500 deaths, over 12,500 of which were reported in the United States [1, 2]. In an experimental rhinovirus infection model, patients with asthma were shown to develop a greater severity of lower respiratory tract symptoms and impaired lung function, which was associated with increased expression of IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) [16]. Allergic asthma models have demonstrated that IL-33, an upstream Th2 cytokine, may enhance influenza-induced exacerbations by dampening the expression of interferon (IFN)-β, a key antiviral mediator [17]. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor α (IL-4Rα), a critical mediator of Th2 signalling, improved their outcomes. The mice were administered intraperitoneally anti-IL-4Rα through either a prophylactic or a therapeutic treatment strategy
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