Mechanisms of increased susceptibility to influenza infection in mouse models of chronic lung diseases

Abstract

Research Doctorate - Doctor of Philosophy (PhD)Influenza infections are of major importance as they have a significant impact on the health of individuals and impart substantial socio-economic ramifications on society. Prevention and treatment of influenza infections are complicated by frequent genetic mutations of the influenza virus. Patients with underlying chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and asthma are more susceptible to influenza infection, and infection with influenza exacerbates these diseases. Therefore, elucidation of the mechanisms underpinning increased susceptibility to influenza in these patients is vital. Here, we established an experimental mouse model of COPD and utilised an existing ovalbumin-induced allergic airways disease (AAD) model to investigate the effects of influenza infection in COPD and asthma, respectively. Influenza infection in experimental COPD resulted in increased viral titre, exaggerated airway inflammation and further impaired lung function. These effects were accompanied by decreased neutrophil influx into the airways, reduced antiviral interferon responses, and the suppression of a range of cytokines and chemokines, including interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IFN-γ-induced protein (IP)-10, macrophage inflammatory protein (MIP)-1α, keratinocyte-derived chemokine (KC, or IL-8 in humans) and interleukin (IL)-10, as well as increased IL-6. This increased susceptibility was mediated by an increase in phosphoinositide 3-kinase (PI3K) protein expression. The inhibition of PI3K effectively reduced viral titre, enhanced antiviral IFNs and improved lung function. Influenza infection in recombinant IL-13-treated or ovalbumin (Ova)-induced AAD models led to increased viral titre, impaired antiviral responses and increased airway hyper-responsiveness (AHR). It also resulted in exaggerated airway inflammation, more severe histopathology, increased mucus secreting cell numbers and increased IL-13. Importantly, we also showed that inhibition of IL-13 by administration of anti-IL-13 (αIL-13) monoclonal antibody during influenza infection reduced viral titre, AHR, eosinophil infiltration and MSCs, which were associated with improved antiviral IFN responses. In summary, these data highlight the important roles of PI3K and IL-13 in the increased susceptibility to influenza infection in experimental models of COPD and asthma, respectively. Such findings offer evidence for new and promising avenues for influenza disease management in these chronic lung diseases. In fact, both PI3K inhibitors and anti-IL-13 antibodies have already entered clinical trials and may be utilised as novel therapeutic approaches for influenza infections in the future