Obesity dysregulates the pulmonary antiviral immune response
Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.
Acknowledgements: M.A. was supported by a Wellcome Trust/Imperial College Clinical Research Training Fellowship. A.J. is supported by an MRC Clinician Scientist Fellowship (MR/Y000935/1). R.J.S. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Sciences (209458/Z/17/Z). S.L.J. is a National Institute for Health Research (NIHR) Emeritus Senior Investigator and received support from the Asthma UK Clinical Chair (Grant CH11SJ), European Research Council Advanced Grants 233015 and 788575, Medical Research Council Centre Grant G1000758 and Asthma UK Centre Grant AUK-BC-2015-01. A.S. is supported by an MRC Clinician Scientist Fellowship (MR/V000098/1). We thank the staff in the Sir Alexander Fleming Building Flow Cytometry Facility for assistance with flow cytometry experiments. This research was supported by the NIHR Imperial Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.