Defects in Innate Immunity Predispose C57BL/6J-Lepr^db/Lepr^dbMice to Infection byStaphylococcus aureus

Abstract

Foot and ankle infections are the most common cause of hospitalization among diabetic patients, and Staphylococcus aureus is a major pathogen implicated in these infections. Patients with insulin-resistant (type 2) diabetes are more susceptible to bacterial infections than nondiabetic subjects, but the pathogenesis of these infections is poorly understood. C57BL/6J-Lepr db /Lepr db (hereafter, db/db) mice develop type 2 diabetes due to a recessive, autosomal mutation in the leptin receptor. We established a S. aureus hind paw infection in diabetic db/db and nondiabetic Lepr +/+ (+/+) mice to investigate host factors that predispose diabetic mice to infection. Nondiabetic +/+ mice resolved the S. aureus hind paw infection within 10 days, whereas db/db mice with persistent hyperglycemia developed a chronic infection associated with a high bacterial burden. Diabetic db/db mice showed a more robust neutrophil infiltration to the infection site and higher levels of chemokines in the infected tissue than +/+ mice. Blood from +/+ mice killed S. aureus in vitro, whereas db/db blood was defective in bacterial killing. Compared with peripheral blood neutrophils from +/+ mice, db/db neutrophils demonstrated a diminished respiratory burst when stimulated with S. aureus. However, bone marrow-derived neutrophils from +/+ and db/db mice showed comparable phagocytosis and bactericidal activity. Our results indicate that diabetic db/db mice are more susceptible to staphylococcal infection than their nondiabetic littermates and that persistent hyperglycemia modulates innate immunity in the diabetic host.

Role of TLR- / NLR-signaling and the associated cytokines involved in recruitment of neutrophils in murine models ofStaphylococcus aureusinfection

“…110 Apparently, the increased inflammatory response observed in db/db mice did not result in resolution of S. aureus infection, which is in accordance with studies where a neutrophil-rich environment actually exacerbated the infection as a result of S. aureus survival within PMNs. 91,108,110 Several studies support the notion that the phagocytosis of bacteria initiates the programmed cell death of PMNs, 111 which are subsequently cleared by infiltrating macrophages. On the other hand, failure of PMNs to undergo apoptosis results in the release of PMN cytotoxic molecules (proteolytic enzymes, antimicrobial proteins and reactive O 2 species) as well as pro-inflammatory mediators.…”

A Humoral Immune Defect Distinguishes the Response to Staphylococcus aureus Infections in Mice with Obesity and Type 2 Diabetes from That in Mice with Type 1 Diabetes

“…Although the impaired innate immune response in diabetes models has been relatively well characterized (13)(14)(15)(16), the adaptive immune response, particularly in the obese, diabetic HFD model, has not been well studied. We observed here that serum IgG levels in HFD-induced T2D mice were less elevated than in controls at 14 days after S. aureus infection (Fig.…”

“…While mouse models of diabetes have been used to show impaired cellular immunity in both macrophages (31) and neutrophils (13,14), humoral immunity has not been well studied in T2D models. In this report, we demonstrate an impaired adaptive immune response in mice with obesity-associated T2D.…”

“…Studies have indicated reduced monocyte function, with macrophages and neutrophils from diabetics showing an impairment in cytokine release, oxidative burst, and phagocytic capability (13)(14)(15)(16). Despite evidence that cells involved in adaptive immunity are causative in the progression of both T1D and T2D (17)(18)(19), few have studied how this involvement may affect responses to infection.…”

Endophthalmitis

“…These important cells are impaired in diabetics. PMN defects in chemotaxis, phagocytosis, and bactericidal activity have been reported in the context of diabetes (Delamaire et al, 1997;Walrand et al, 2004) and PMN from diabetic mice and humans are incapable of phagocytizing and killing both S. aureus and K. pneumoniae (Lin et al, 2006;Park et al, 2009). These defects in the ability of PMNs to clear bacteria that are destined to cross a compromised blood retinal barrier may also contribute to the development and pathogenesis of EE, but this has not been scientifically analyzed.…”