Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen

Abstract

Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet-induced obesity

“…These increases in blood glucose were approximately 15–30 times smaller than the increases observed in obesity‐independent hyperglycemia models, where blood glucose typically increases by more than threefold compared to normoglycemic mice (Javid et al . , ). Surprisingly, infected mice fed ND weighed 8% more ( p < 0.05) on average than mock‐infected controls at time of sacrifice (Figure a).…”

“…We recently found that obesity‐independent hyperglycemia impairs innate immune responses to male C3H/HeN mice infected with 1 × 10 4 of B. burgdorferi strain GCB726 (Javid et al . , ). Therefore, experiments investigating the effects of DIO on innate immune responses to B. burgdorferi infection were also performed with male C3H/HeN mice infected with 1 × 10 4 GCB726, to facilitate comparison of the effects of obesity and hyperglycemia on innate immune responses.…”

“…We found recently that severe obesity‐independent hyperglycemia is also associated with impaired B. burgdorferi tissue clearance and uptake by neutrophils (Javid et al . , ). However, unlike the results reported here, obesity‐independent hyperglycemia does not increase the severity of inflammatory pathology in B. burgdorferi infection and does not act synergistically or cooperatively to suppress innate immune responses (Javid et al .…”

“…However, unlike the results reported here, obesity‐independent hyperglycemia does not increase the severity of inflammatory pathology in B. burgdorferi infection and does not act synergistically or cooperatively to suppress innate immune responses (Javid et al . , ). This, together with our observation that DIO was associated with only mild hyperglycemia, suggest that DIO exerts distinct and more severe, wide‐ranging effects on the outcomes of B. burgdorferi infection and host immune responses than hyperglycemia alone.…”

“…We and others have recently found that obesity‐independent hyperglycemia and obesity‐independent hypercholesteremia in mice are associated with disrupted innate and adaptive immune responses to the Lyme disease pathogen Borrelia burgdorferi and impaired control of bacterial burden and/or B. burgdorferi DNA clearance from tissues (Toledo, Monzón, Coleman, Garcia‐Monco, & Benach, ; Javid et al . , ). Therefore, metabolic conditions associated with obesity can affect B. burgdorferi infection in mouse models.…”