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

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.

A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19

“…In the non-alveolar epithelium, damaged ciliated cells lead to reduced mucociliary clearance capacity ( 282 , 283 ), and compromised integrity of tight junctions increases paracellular flux of glucose into the ASL ( 117 , 207 ), escalating the damage through the numerous mechanisms described before (see Figure 20 ). This is in agreement with a recent publication on IAV infection showing that elevated glucose prior to viral infection increases virus-induced pulmonary barrier damage ( 284 ). Host cell damage together with elevated glucose turns negative feedback homeostatic mechanisms into a positive feedback loop of pathological processes.…”

Susceptibility for Some Infectious Diseases in Patients With Diabetes: The Key Role of Glycemia

“…The influenza A virus (IAV) induces a self-limited infection in most patients, which is characterized by several symptoms such as myalgia, fever, and dry cough ( 130 ). Nevertheless, patients with diabetes experience a more severe type of this disease ( 131 ) that is represented by a triple risk of hospitalization and double risk of fatality compared with non-diabetic sufferers ( 132 ). Despite the fact that IAV infects upon 15% of the world's population every year ( 133 ), the full mechanisms underlying its pathogenesis, especially on patients with diabetes, remain thus far inconclusive.…”

“…Despite the fact that IAV infects upon 15% of the world's population every year ( 133 ), the full mechanisms underlying its pathogenesis, especially on patients with diabetes, remain thus far inconclusive. In this sense, Hulme et al ( 132 ) reported that the IAV infection in hyperglycemic conditions increases the endothelial damage leading to a pronounced inflammatory response; this explains, at least in part, the severity of the symptoms in patients with diabetes ( 132 ). In support of this notion, Kohio and Adamson ( 134 ) reported an enhanced IAV replication rate in pulmonary epithelial cells under elevated glucose concentrations in vitro .…”

“…Admittedly, the specific mechanisms that underline susceptibility factors for viral infections development in patients with diabetes ( Table 2 ) are poorly understood. However, an experimental study ( 132 ) that used an in vitro and in vivo model of pulmonary epithelial-endothelial cells exposed to a high glucose concentration (12 mM) demonstrated an increased barrier damage after co-cultured cells were infected with IAV; this, in turn, augmented pulmonary edema associated with a pro-inflammatory response ( 132 ). Thus, controlling hyperglycemia seems to be important for hospitalized patients with severe viral infections and diabetes ( 144 ).…”

A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants

“…Viral and host RNA was extracted from mouse lung samples, cDNA was synthesised, and real-time PCR was performed as described previously ( Hulme et al, 2020 ). Forward and reverse primers used in the present study are supplied in Supplementary file 1 .…”