The effect of obesity on the host innate immune response to influenza infection
Creators: name: Almond, Mark
Publisher: name: Imperial College London
Year: 2015

description: Background: We live in an ‘obesogenic environment’ in which overconsumption of affordable, energy-dense, processed foods has resulted in the prevalence of obesity more than doubling since 1980, such that it is now the commonest nutritional disorder worldwide. In March 2009, a novel strain of influenza A virus (pH1N1/09) emerged in Mexico, rapidly spreading around the world to cause the first influenza pandemic of the 21st century. For the first time during an influenza pandemic, obesity was convincingly identified as a novel, independent risk factor for multiple markers of disease severity, including hospitalisation, intensive care unit admission and death following infection. The aim of this project was to investigate the mechanisms underlying this increased susceptibility to severe outcomes following pH1N1/09 infection in morbidly obese individuals using primary human tissues. We hypothesised that obesity-associated hyper-leptinaemia would increase constitutive expression of the negative regulator, suppressor of cytokine signalling 3 (SOCS3), in key pulmonary structural and immune cells and that this, in turn, would attenuate interferon (IFN) expression and signal transduction, thus reducing induction of IFN stimulated genes (ISGs), the main antiviral effectors. Methodology: A case-control study design was adopted in which bronchial epithelial cells (hBECs), bronchoalveolar lavage (BAL) cells, peripheral blood mononuclear cells (PBMCs) and peripheral blood dendritic cells (DCs) were isolated from 15 morbidly obese individuals (body mass index (BMI) ≥ 35 kg/m2) and 15 age, gender and ethnicity-matched healthy weight (‘lean’) controls (BMI 20-25 kg/m2) by bronchoscopy and venesection to allow comparison of the type I and III IFN and pro- inflammatory cytokine responses following pandemic and seasonal influenza infection. Viral replication, ISG and SOCS expression profiles were also quantified in the primary cells and the constitution of the inflammatory environment in which the cells reside was evaluated through measurement of adipokines, cytokines, acute phase proteins and chemokines. Results: BAL cells from morbidly obese individuals exhibited deficient type I and III IFN responses to both pandemic and seasonal influenza virus infection. This IFN- deficiency was BAL cell specific and therefore not observed following infection of primary hBECs, PBMCs or DCs. Although unlikely, it is possible that the observed IFN deficiency may have been due to the confounding effects of the general anaesthesia that the obese subjects underwent during their bronchoscopy. Elevated leptin levels were observed in the lung and serum of the obese subjects; however, baseline constitutive SOCS3 mRNA expression was not increased in the obese subjects and we were unable to demonstrate leptin-induced upregulation of SOCS3. For the first time, we report relatively high expression of the lesser-studied adipokines resistin, visfatin and adipsin in the lung and nose. Additionally, we report that the acute phase protein, C-reactive protein (CRP), a biomarker of inflammation, was significantly elevated in the BAL fluid of the obese subjects. Conclusion: Obesity-associated BAL cell IFN deficiency may contribute to the increased susceptibility to severe outcomes seen in the obese population following influenza infection.