Superbug Virulence in Diabetic Infections Linked to High Glucose and Poor Immune Response

The combination of immune dysfunction and high levels of blood glucose in people with uncontrolled diabetes appear to provide an ideal environment for a common type of superbug to thrive unchecked and do its worst damage, according to new research by scientists at the University of Pittsburgh (Pitt) School of Medicine.

The researchers’ studies found that Staphylococcus aureus—a bacterium that is often is resistant to antibiotics—thrives in glucose-rich diabetic conditions, which trigger activation of some of its most virulent features. The results indicated that a lack of insulin in addition prevents the immune system from responding to the infection. “This explains why a wound or cut in a patient with diabetes really must be treated aggressively,” said Anthony Richardson, PhD, associate professor in Pitt’s department of microbiology & molecular genetics. “The immune system needs help recognizing and clearing the infection before it’s able to take hold.” Richardson is senior author of the team’s published paper in Science Advances, which is titled, “Lack of nutritional immunity in diabetic skin infections promotes Staphylococcus aureus virulence.”

It’s estimated that about 11% of people in the United States have diabetes, and more than a third of all adults have prediabetes. The global incidence of diabetes is also rapidly increasing, and it is predicted that more than 590 million people will be affected by 2035, the researchers wrote. One hallmark feature of diabetes is elevated blood levels of glucose, which results either when the body doesn’t produce enough insulin, or when there is poor response to the insulin that is produced.

Up to a third of people with diabetes will develop diabetic foot ulcers, which can lead to foot infection and leg amputation, the researchers said. “One of the most common infections in individuals with diabetes are skin and soft tissue infections (SSTIs) that often manifest as foot ulcers.” S. aureus is the bacterium that is most often is associated with these types of invasive infections, especially in people with poorly controlled diabetes, and rates of S. aureus infections and diabetes have grown in parallel over the past three decades. “SSTIs in people with diabetes are often polymicrobial; however, S. aureus is the most commonly isolated pathogen from diabetic SSTI,” the team continued.

Prior studies have indicated that the severity of diabetic infections is linked with defects in both innate and adaptive immunity. But while immune suppression in diabetic infections has been well reported, the investigators noted, “ … to our knowledge, there have been few studies that address how hyperglycemia in diabetic infections influences the virulence potential of bacterial pathogens.”

Prior studies by lead author Lance Thurlow, PhD, who conducted the newly reported research at Pitt and who is now at the University of North Carolina at Chapel Hill, had shown that S. aureus had evolved two glucose transporters, glcA and glcC, which are in addition to the two that are already common to most staphylococcal species. This gives S. aureus an advantage over other bacteria in making use of the excess blood sugar in diabetic conditions, to proliferate.

In their new study, Richardson, Thurlow, and colleagues carried out a series of experiments with Streptozotocin (STZ)-diabetic and nondiabetic mice, using strains of staphylococcus with and without the extra transporters. They found that in the diabetic mice, the strain of S. aureus with four glucose transporters quickly formed biofilms and activated pathways that increased virulence. In contrast, diabetic mice infected with strains of staphylococcus that didn’t have the extra glucose transporters developed less invasive infections, though their immune systems were still slower to respond than those of the nondiabetic animals. “Specifically, we show that the recent acquisition of glcA and glcC by S. aureus is essential for full toxin production and virulence potential in hyperglycemic SSTIs,” they wrote.

The results confirmed that while the immune systems of nondiabetic animals were generally able to contain and fight S. aureus infection, the immune systems of the diabetic mice were particularly slow to respond, resulting in unchecked infection and severe diabetic ulcers.

Their investigations showed that the diabetic mice displayed a dysfunctional immune system response, with immune system phagocytes failing to express glucose transporters necessary to take in enough glucose to power the mechanisms that are needed to clear the infection. “ … we show that the lack of GLUT-1/-3 expression on infiltrating phagocytes from STZ-treated, insulin-deficient animals correlates with their inability to mount an effective oxidative burst and clear the infection,” the team wrote.

This also meant that there was extra glucose for the S. aureus bacteria. “The lack of glucose consumption by these phagocytes coupled with total body hyperglycemia results in an infection environment that is replete with the excess glucose,” they wrote, and this enabled the S. aureus bacteria to reach much higher densities in wounds. Interestingly, diabetic mice that were given a drug that lowers blood sugar were able to contain the infection almost as well as were the regular mice.

The researchers suggested their combined results indicated that “ … immune dysfunction in STZ-treated animals primarily results in increased bacterial burdens, whereas elevated tissue glucose is responsible for increased S. aureus virulence factor production … The recent acquisition of the glucose transporters GlcA and GlcC significantly contributes to S. aureus virulence, particularly in hyperglycemic tissue.” … we can now begin to understand why patients with diabetes suffer specifically from S. aureus infections so frequently.”

Knowing the mechanism that is used by S. aureus uses to cause serious infections in people with diabetes could lead to treatments that capitalize on the bacteria’s hunger for glucose, tricking it into consuming a toxic analogue, suggested Richardson. “But we also can’t lose sight of the need to prevent and control diabetes,” he added. “If we can keep people from developing diabetes and help people who have it to control their blood sugar, then S. aureus will have a much more difficult time causing such terrible infections.”