Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

Journal of Translational Medicine

Kenji M Cunnion¹  Julius O Nyalwidhe⁴  Neel K Krishna¹  Reuben D Rohn²  Charlene G Echague³  Pamela S Hair³ 

[1] Children's Specialty Group, 601 Children's Lane, Norfolk, VA, USA;Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA, USA;Department of Pediatrics, Eastern Virginia Medical School, 855 West Brambleton Avenue, Norfolk, VA, USA;Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, Virginia, USA

关键词: Polymicrobial infection;    Immune evasion;    Hyperglycemia;    Staphylococcus aureus;    Complement C3;   

Others  :  1206046
DOI  :  10.1186/1479-5876-10-35

 received in 2011-12-07, accepted in 2012-03-05,  发布年份 2012

【 摘 要 】

Background

Diabetic patients are at increased risk for bacterial infections; these studies provide new insight into the role of the host defense complement system in controlling bacterial pathogens in hyperglycemic environments.

Methods

The interactions of complement C3 with bacteria in elevated glucose were assayed for complement activation to opsonic forms, phagocytosis and bacterial killing. C3 was analyzed in euglycemic and hyperglycemic conditions by mass spectrometry to measure glycation and structural differences.

Results

Elevated glucose inhibited S. aureus activation of C3 and deposition of C3b and iC3b on the bacterial surface. S. aureus-generated C5a and serum-mediated phagocytosis by neutrophils were both decreased in elevated glucose conditions. Interestingly, elevated glucose increased the binding of unactivated C3 to S. aureus, which was reversible on return to normal glucose concentrations. In a model of polymicrobial infection, S. aureus in elevated glucose conditions depleted C3 from serum resulting in decreased complement-mediated killing of E. coli. To investigate the effect of differing glucose concentration on C3 structure and glycation, purified C3 incubated with varying glucose concentrations was analyzed by mass spectrometry. Glycation was limited to the same three lysine residues in both euglycemic and hyperglycemic conditions over one hour, thus glycation could not account for observed changes between glucose conditions. However, surface labeling of C3 with sulfo-NHS-biotin showed significant changes in the surface availability of seven lysine residues in response to increasing glucose concentrations. These results suggest that the tertiary structure of C3 changes in response to hyperglycemic conditions leading to an altered interaction of C3 with bacterial pathogens.

Conclusions

These results demonstrate that hyperglycemic conditions inhibit C3-mediated complement effectors important in the immunological control of S. aureus. Mass spectrometric analysis reveals that the glycation state of C3 is the same regardless of glucose concentration over a one-hour time period. However, in conditions of elevated glucose C3 appears to undergo structural changes.

【 授权许可】

   
2012 Hair et al; licensee BioMed Central Ltd.

【 图 表 】

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