It has been known for decades that diabetics and pre-diabetics with high levels of blood sugar (hyperglycemia) are at a substantially increased risk of developing severe lung disease if they become infected with viruses such as influenza, as well as with bacteria and fungi.
This mysterious phenomenon became even more pressing when the COVID-19 pandemic began in early 2020. It became clear that diabetics were at a much higher risk of coming down with severe, even fatal, lung disease after developing a serious form of the virus. However, no one understood why. In fact, about 35% of victims of the coronavirus who died during the pandemic had diabetes.
Now, research conducted at the Weizmann Institute of Science in Rehovot has revealed how, in diabetics, high levels of blood sugar disrupt the function of key cell subsets in the lungs that regulate the immune response. It also identifies a potential strategy for reversing this susceptibility and saving lives.
It has just been published in the prestigious journal Nature under the title “Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.” The study was led by Drs. Samuel Nobs, Aleksandra Kolodziejczyk, and Suhaib Abdeen are in Prof. Eran Elinav’s team in his systems immunology department lab.
Conducting the research
The team subjected multiple mouse models of type-1 and type-2 diabetes to a variety of viral lung infections. Just as in diabetics, in all the rodent models, the diabetic mice developed a severe, fatal lung infection following exposure to lung pathogens such as the flu.
The immune reaction, which in nondiabetics eliminates the infection and drives tissue healing, was severely impaired in the diabetic mice, leading to uncontrolled infection, lung damage, and eventual death.
To decode the basis of this elevated risk, the team performed an evaluation of gene expression on the level of individual cells in more than 150,000 single lung cells of infected diabetic and nondiabetic mice.
The researchers also conducted extensive experiments involving immune and metabolic mechanisms and an in-depth assessment of immune cell gene expression in infected diabetic mice.
In the diabetic mice, they identified dysfunction in certain lung dendritic cells, the immune cells that orchestrate a targeted immune response against pathogenic infection.
“High blood-sugar levels severely disrupt certain subsets of dendritic cells in the lung, preventing these gatekeepers from sending the molecular messages that activate the critically important immune response,” said postdoctoral fellow Nobs, the study’s first author. “As a result, the infection rages on, uncontrolled.”
Importantly, the scientists discovered how high sugar levels in diabetic mice disrupt the normal function of lung dendritic cells during infection. Altered sugar metabolism in these cells led to the accumulation of metabolic byproducts that markedly disrupted the normal regulation of gene expression, leading to abnormal immune-protein production.
“This could explain why the functioning of these cells is disturbed in diabetes and why the immune system is unable to generate an effective anti-infection defense,” added Kolodziejczyk, a postdoctoral fellow who co-led the study.
The scientists next wanted to find ways to prevent the harmful effects of high sugar levels in lung dendritic cells to lower the infection risk in diabetic animals.
They found that tight control of blood sugar levels by insulin supplementation prompted the dendritic cells to regain their capacity to generate a protective immune response that could prevent the cascade of events leading to a severe, life-threatening viral lung infection.
If small molecules reversing the sugar-induced regulatory impairment were given, they corrected the dendritic cells’ dysfunction and enabled them to generate a protective immune response despite the presence of high sugar levels.
“Correcting blood sugar levels or using drugs to reverse the gene regulatory impairment induced by high sugar enabled our team to get the dendritic cells’ function back to normal,” noted Abdeen, a senior intern who co-supervised the study.
“This was very exciting because it means that it might be possible to block diabetes-induced susceptibility to viral lung infections and their devastating consequences.”
With more than 500 million people around the world affected by diabetes and diabetes incidence expected to rise, the new research has significant, promising clinical implications.
“Our findings provide, for the first time, an explanation as to why diabetics are more susceptible to respiratory infection,” Elinav concluded.
“Controlling sugar levels may make it possible to reduce this pronounced diabetes-associated risk. In diabetic patients whose sugar levels are not easily normalized, small molecule drugs may correct the gene alterations caused by high sugar levels, potentially alleviating or even preventing severe lung infection. Local administration of such treatments by inhalation may minimize adverse effects while enhancing effectiveness, and merits future human clinical testing.”
