High glucose levels increase influenza-associated damage to the pulmonary epithelial-endothelial barrier.

Katina D Hulme,Linda A Gallo,Katharina Ronacher,Keng Yih Chew,Conor J Bloxham,Kirsty R Short,Zhixuan Loh,Limin Yan,Helle Bielefeldt-Ohmann,Rebecca J Marshall,Kyle R Upton,Sumaira Z Hasnain

doi:10.7554/elife.56907

Abstract

Diabetes mellitus is a known susceptibility factor for severe influenza virus infections. However, the mechanisms that underlie this susceptibility remain incompletely understood. Here, the effects of high glucose levels on influenza severity were investigated using an in vitro model of the pulmonary epithelial-endothelial barrier as well as an in vivo murine model of type II diabetes. In vitro we show that high glucose conditions prior to IAV infection increased virus-induced barrier damage. This was associated with an increased pro-inflammatory response in endothelial cells and the subsequent damage of the epithelial junctional complex. These results were subsequently validated in vivo. This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in individuals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections.

Highlights

Every year influenza A virus (IAV) infects 5–15% of the world’s population (Goeijenbier et al, 2017; Stohr, 2002)
We show that compared to normal glucose concentrations, elevated glucose levels prior to IAV infection increase virus-induced barrier damage, both in vitro and in vivo, and that this damage is associated with endothelial-driven inflammation
The development of an elevated transepithelial/endothelial electrical resistance (TEER) was not affected by the differing glucose concentrations (Figure 1—figure supplement 1), and culture of primary endothelial cells in Roswell Park Memorial Institute medium (RPMI) media did not affect their endothelial phenotype (Figure 1—figure supplement 2) as has been previously described (Short et al, 2016)

Summary

Introduction

Every year influenza A virus (IAV) infects 5–15% of the world’s population (Goeijenbier et al, 2017; Stohr, 2002). Influenza virus causes an acute and self-limiting disease. Influenza virus can cause severe disease in individuals with certain chronic medical conditions, including diabetes mellitus (Short et al, 2014). Upon infection with influenza virus, patients with diabetes have triple the risk of hospitalisation, quadruple the risk of admission to the intensive care unit and double the risk of a fatal outcome compared to individuals with no underlying illness (Allard et al, 2010; Wilking et al, 2010). The remaining ~90% of cases belong to the T2D category which is characterised by relative insulin deficiency as a result of pancreatic b-cell dysfunction and insulin resistance (Chatterjee et al, 2017; Defronzo, 2009). Diabetes is associated with complications that affect multiple organ systems

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