Cargando…

Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

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 g...

Descripción completa

Detalles Bibliográficos
Autores principales: Hair, Pamela S, Echague, Charlene G, Rohn, Reuben D, Krishna, Neel K, Nyalwidhe, Julius O, Cunnion, Kenji M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328285/
https://www.ncbi.nlm.nih.gov/pubmed/22390383
http://dx.doi.org/10.1186/1479-5876-10-35
_version_ 1782229719622615040
author Hair, Pamela S
Echague, Charlene G
Rohn, Reuben D
Krishna, Neel K
Nyalwidhe, Julius O
Cunnion, Kenji M
author_facet Hair, Pamela S
Echague, Charlene G
Rohn, Reuben D
Krishna, Neel K
Nyalwidhe, Julius O
Cunnion, Kenji M
author_sort Hair, Pamela S
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3328285
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-33282852012-04-18 Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus Hair, Pamela S Echague, Charlene G Rohn, Reuben D Krishna, Neel K Nyalwidhe, Julius O Cunnion, Kenji M J Transl Med Research 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. BioMed Central 2012-03-05 /pmc/articles/PMC3328285/ /pubmed/22390383 http://dx.doi.org/10.1186/1479-5876-10-35 Text en Copyright ©2012 Hair et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Hair, Pamela S
Echague, Charlene G
Rohn, Reuben D
Krishna, Neel K
Nyalwidhe, Julius O
Cunnion, Kenji M
Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title_full Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title_fullStr Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title_full_unstemmed Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title_short Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus
title_sort hyperglycemic conditions inhibit c3-mediated immunologic control of staphylococcus aureus
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328285/
https://www.ncbi.nlm.nih.gov/pubmed/22390383
http://dx.doi.org/10.1186/1479-5876-10-35
work_keys_str_mv AT hairpamelas hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus
AT echaguecharleneg hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus
AT rohnreubend hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus
AT krishnaneelk hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus
AT nyalwidhejuliuso hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus
AT cunnionkenjim hyperglycemicconditionsinhibitc3mediatedimmunologiccontrolofstaphylococcusaureus