Diabetes exacerbates infection severity due to hyperinflammation rather than neutrophil defects (INM7P.425)

Abstract

Abstract Patients with diabetes mellitus are at increased risk of dying from Gram negative bacterial infections. This excess mortality is often attributed to immune suppression, including neutrophil dysfunction. However, diabetic hosts also exhibit increased inflammatory responses to LPS. Here we show that lethal infections with Acinetobacter baumannii in diabetic mice are driven by LPS interactions with TLR4, as opposed to neutrophil defects. Mice made diabetic either by streptozotocin (Type 1) or diet induced obesity (Type 2) were hypersusceptible to lethality from A. baumannii bacteremia, whereas mice made neutropenic by anti-Ly6G administration were not more susceptible to infection. Diabetic infected mice developed severe septic shock, with hypothermia, medical acidosis, and marked elevations in inflammatory cytokines, compared to non-diabetic mice. Diabetic mice with impaired or absent TLR4 function, however, were protected against lethal infection and did not develop sepsis. Collectively, these results suggest that enhanced lethality of A. baumannii infection in diabetic mice is not driven by diabetes-related abrogation of neutrophil function. Rather, diabetic mice are more prone to progression to severe sepsis syndrome and are protected from this progression by impairment of TLR4 function. Short term abrogation of TLR4 signaling is a promising therapeutic approach to the treatment of A. baumannii, and possibly other Gram negative infections in diabetic hosts.