Diabetes mellitus is a global health concern, affecting approximately 537 million adults. Diabetes is a susceptibility factor for severe influenza virus infections, however, the mechanisms linking the two remain undefined. One possibility is that hyperglycaemia, a key characteristic of diabetes, results in trained immunity, ultimately resulting in an uncontrolled and harmful immune response to influenza virus infection. Trained immunity describes the epigenetic and metabolic changes within innate immune cells that occur after exposure to a stimulus. These changes culminate in altered responsiveness when immune cells have been exposed to a second, unrelated stimulus (such as viral infection). Hyperglycaemic-induced trained immunity has previously been described in response to lipopolysaccharide and interferon-γ (IFN-γ) stimulation. However, to date, the effect of diabetic training in response to influenza and viral ligands is yet to be quantified.
Here, we demonstrate that healthy donor peripheral blood mononuclear cells (PBMCs) with an ex vivo history of hyperglycaemia display a heightened proinflammatory response to stimulus with influenza virus and viral mimetic R848. Specifically, these PBMCs produced higher levels of TNF-α in response to influenza virus stimulation and higher levels of proinflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ, in response to the viral mimetic. Similarly, monocytes from 17 individuals living with diabetes produced enhanced TNF-α and IFN-γ relative to healthy controls (n=11) when exposed to influenza and R848 ex vivo. This phenomenon was also observed in natural killer (NK) cells, where NK cells from diabetic patients expressed higher levels of TNF-α, IFN-γ, CD69 and granzyme B when stimulated with influenza virus or viral mimetic compared to non-diabetic controls.
This study provides the first evidence suggesting that innate immune cells from people with diabetes mount a higher inflammatory response to viral stimulation ex vivo; the cause of which requires further investigation. Nevertheless, these data provide an important insight into the interactions of increasingly prevalent non-communicable diseases such as diabetes with viral infections like influenza. Ultimately, these data highlight the importance of understanding the intricate nature of the innate immune system, and how co-morbidities can affect the functioning of this system.