Abstract
Many bacteria regulate the expression of virulence factors via carbon catabolite responsive elements. In Gram-positive bacteria, the predominant mediator of carbon catabolite repression is the catabolite control protein A (CcpA). Hyperglycemia is a widespread disorder that predisposes individuals to an array of symptoms and an increased risk of infections. In hyperglycemic individuals, the bacterium Staphylococcus aureus causes serious, life-threatening infections. The importance of CcpA in regulating carbon catabolite repression in S. aureus suggests it may be important for infections in hyperglycemic individuals. To test this suggestion, hyperglycemic non-obese diabetic (NOD; blood glucose level ≥20 mM) mice were challenged with the mouse pathogenic S. aureus strain Newman and the isogenic ccpA deletion mutant (MST14), and the effects on infectivity were determined. Diabetic NOD mice challenged with the ccpA deletion mutant enhanced the symptoms of infection in an acute murine pneumonia model relative to the parental strain. Interestingly, when diabetic NOD mice were used in footpad or catheter infection models, infectivity of the ccpA mutant decreased relative to the parental strain. These differences greatly diminished when normoglycemic NOD mice (blood glucose level ≤ 10 mM) were used. These data suggest that CcpA is important for infectivity of S. aureus in hyperglycemic individuals.
Highlights
Diabetes mellitus is a common endocrinopathy in both household animals and humans (Bennett, 2002; Shaw et al, 2010)
The bacterial loads in lung tissue and broncho-alveolar lavage (BAL) were similar in the pneumonia model (Figure 1A); the swelling of footpads displayed comparable kinetics and maxima (Figure 1B); and the edema formation rates and bacterial loads in the catheter lumen and surrounding tissues were indistinguishable in the catheter infection model (Figure 1C)
For most of these regulators (i.e., CcpE, CodY, and RpiRc), an attenuating effect on infectivity of S. aureus is observed in murine infection models (Montgomery et al, 2012; Ding et al, 2014; Hartmann et al, 2014; Balasubramanian et al, 2016; Gaupp et al, 2016)
Summary
Diabetes mellitus is a common endocrinopathy in both household animals and humans (Bennett, 2002; Shaw et al, 2010). S. aureus infections in diabetic mice are associated with increased inflammation, endothelial injury, and blood coagulation (Rich and Lee, 2005; Tsao et al, 2006; Hanses et al, 2011). The killing of S. aureus in the diabetic host is impaired due to a diminished leukocytic respiratory burst (Rich and Lee, 2005). While these studies focused on host factors involved in the immune response, little is known about the bacterial factors that mediate S. aureus success in colonizing and causing infections in diabetic foot ulcerations (DFU). The importance of PIA and EDIN in the infectivity of S. aureus in DFU is unknown, and it remains to be seen whether PIA and EDIN are expressed in the diabetic environment relative to normoglycemic conditions
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