Modeling Asthma and Influenza Co-morbidity in C57BL/6J Mice

Commonly referred to as a disease, asthma is a syndrome¹ that affects over 235 million of the world’s population.² Allergic asthma is the most prevalent type of asthma and results from exposures to environmental factors such as pollen, house dust mite and cockroach antigens, and fungi.³ Fungal antigens are common sensitizing allergens affecting 25% of persistent asthmatics and can cause life threatening asthma attacks.⁴ The development of an accurate model of allergic asthma is challenging because mice do not naturally develop asthma and there are differences between mouse and human respiratory systems.⁵ The selection of the mouse asthma model system is largely dependent on the experimental question since the output may vary with the antigen used. A fungal asthma model using Aspergillus fumigatus conidia used in native form and natural route of entry into the airways of mice, described in detail elsewhere,^6-8 has been shown to elicit all the hallmarks of human disease including airways hyperresponsiveness, eosinophilic inflammation, mucus hypersecretion, and airway wall remodeling events.⁹

Influenza affects millions worldwide every year. Genetic alterations that occur in influenza viruses by antigenic drifts and shifts, and re-assortments in common hosts can result in a novel virus with the potential to cause a pandemic. The influenza pandemic of 1918 (Spanish Flu) claimed over 50 million lives mostly of young adults.¹⁰ The first influenza pandemic of the 21^st century occurred in 2009. Although the 2009 influenza pandemic was not as severe as that of 1918, approximately 90 million people were infected¹¹ of which a little over 200,000 died.¹² Hospitalized patients included those with underlying diseases such as obesity, cardiovascular and metabolic disease, asthma, COPD, and diabetes.^13-16 Although asthma was identified as a risk factor for severe influenza morbidity,^17,18 asthmatics were less likely to be admitted to the intensive care unit and die compared to patients without asthma.^19,20 The reasons for these seemingly counterintuitive findings are unknown. Therefore, a reliable animal model system was necessary to study the intersection of these two diseases.

Since other respiratory viruses such as rhinovirus and respiratory syncytial virus (RSV) have been shown to induce asthma, existing animal models of asthma and influenza explored whether influenza virus infections induces the development of asthma.²¹ The airways, lung parenchymal tissue, and the immune responses are different during acute allergic asthma exacerbations and chronic stable asthma. Therefore, models that can explore how influenza virus infections intersect allergic asthma in each situation are necessary to understand the underlying mechanisms of asthma and influenza comorbidities. This protocol describes a mouse model that can recapitulate these two scenarios.