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Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils
Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
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2004 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 112, no 2, 109-118 p.Article in journal (Refereed) Published
Abstract [en]

S. epidermidis is the most common isolate in foreign body infections. The aim of this study was to understand why S. epidermidis causes silent biomaterial infections. In view of the divergent inflammatory responses S. epidermidis and S. aureus cause in patients, we analyzed how they differ when interacting with human neutrophils. Neutrophils interacting with S. epidermidis strains isolated either from granulation tissue covering infected hip prostheses or from normal skin flora were tested by measuring the oxidative response as chemiluminescence and apoptosis as annexin V binding. Different S. aureus strains were tested in parallel. All S. epidermidis tested were unable to modulate the oxidative reaction in response to formyl-methionyl-leucyl-phenylalanine (fMLP) and did not provoke, but rather inhibited, apoptosis. In contrast, some S. aureus strains enhanced the oxidative reaction, and this priming capacity was linked to p38-mitogen-activated-protein-kinase (p38-MAPK) activation and induction of apoptosis. Our results may explain why S. epidermidis is a weak inducer of inflammation compared to S. aureus, and therefore responsible for the indolent and chronic course of S. epidermidis biomaterial infections.

Place, publisher, year, edition, pages
2004. Vol. 112, no 2, 109-118 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-23732DOI: 10.1111/j.1600-0463.2004.apm1120205.xLocal ID: 3239OAI: oai:DiVA.org:liu-23732DiVA: diva2:244047
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Coagulase-negative staphylococci in prosthetic hip infections
Open this publication in new window or tab >>Coagulase-negative staphylococci in prosthetic hip infections
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

More than 11,000 primary total hip replacements were performed in Sweden in the year 2000, corresponding to 125 primary total hip replacements per 100,000 inhabitants, according to The Swedish Total Hip Replacement Register. In general, this procedure provides highly satisfactory results. The most common complications associated with prosthetic hip joints are aseptic biomechanical failures and infections. Delayed low-grade infections occur most often, and they are also the most difficult to distinguish from aseptic mechanical failures because of similar symptoms.

During the period 1994 to 2001, a prospective study was conducted to compare inflammatory markers in blood, synovial fluid, and histopathological specimens in patients diagnosed with aseptic or septic loosening of hip prostheses. Coagulase-negative staphylococci (CoNS) were found to be the most common pathogens in the patients with prosthetic hip joint infections.

Further characterisation of the CoNS revealed that patients were co-infected with the following: (i) CoNS and other bacterial species, (ii) various CoNS species, and (iii) different S. epidermidis clones. Expression of the icaADB gene complex, which is important for the biofilm mode-of-growth characteristic of S. epidermidis, was not necessary to allow S. epidermidis to infect orthopaedic prostheses. The majority of the S. epidermidis isolates, both from prostheses and normal bacteria flora, were able to bind to at least one of the extracellular matrix proteins we tested, this adhesion ability is a probable virulence factor. Histologically, the extent of cell infiltration differed between aseptic and septic loosening of prostheses, and neutrophils in tissue at a rate of ≥ 5 cells/high power field greatly favoured infection. Periprosthetic tissue contained the cells that are required not only for an innate, but also a specific, immune response, which supports the theory that the limited systemic inflammatory response in infections of hip prostheses is not due to failure of inflammatory cells to reach the infected area, but is more likely caused by an inadequate response to the infecting organisms.

Therefore, we studied the interactions between neutrophils and S. epidermidis (the most common CoNS species in hip prosthetic infections). Neutrophils phagocytosed both surfaceadherent and planktonic S. epidermidis, but they ingested adherent S. aureus isolates more readily than they consumed adherent S. epidermidis. The reduced phagocytosis of S. epidermidis by neutrophils is viewed as a virulence factor, together with the lack of an ability to prime or sufficiently activate the neutrophil oxidase, and thereby evade adequate killing by neutrophils. The weak oxidative activation agrees with the low inflammatory response seen in patients with S. epidermidis infections related to implanted devices. Furthermore, both planktonic and adherent S. epidermidis delayed neutrophil apoptosis, and we suggest that this leads to the accumulation of neutrophils at the site of inflammation. We propose that the complex interplay between the S. epidermidis-induced delay in apoptosis in neutrophils and the interaction of S. epidermidis-containing neutrophils with macrophages in periprosthetic tissue has negative impact on the outcome in patients with prosthetic hip joint infections, resulting in low grade inflammation, tissue damage, and finally loosening of the prosthesis.

Abstract [sv]

Fler än 11.000 primära totala höftutbytesoperationer utfördes i Sverige 2000, detta motsvarar 125 operationer per 100.000 innevånare enligt Svenska Nationella Höftplastikregistret. Höftprotesoperationer uppvisar vanligen mycket goda resultat, men komplikationer förekommer där de vanligaste är aseptisk lossning respektive infektioner i anslutning till proteserna. De sena, läggrarliga infektionerna är vanligast, och det är också dessa, som är svårast att skilja från mekaniska lossningar på grund av liknande symtom.

Under perioden 1994 till 2001 utfördes en prospektiv studie för att jämföra inflammatoriska markörer i blod, ledvätska och i vävnad hos patienter med diagnosen aseptisk respektive septisk (infektiös) lossning av höftproteser. Koagulas-negativa stafylokocker (KNS) var den vanligaste sjukdomsframkallande bakterien hos patienter med infekterade höftproteser. Vidare karakterisering av KNS visade att höftprotespatienterna var infekterade enligt följande: (i) KNS plus andra bakteriella arter, (ii) olika KNS arter, och (iii) olika kloner av S. epidermis. Uttryck av icaADB gen komplexet, som är viktigt för utvecklandet av biofilm vilket är ett sätt att växa som är karakteristiskt för S. epidermidis bakterier, visade sig inte vara nödvändigt för att utveckla protesinfektion med S. epidermidis. Majoriteten av S. epidermidis, både de som isolerades från höftproteser respektive från hudens normalflora, hade förmåga att binda in till åtminstone ett av de extracellular matrix proteiner som testades. Denna adhesionsförmåga är en trolig virulensfaktor. Histologiskt (i vävnaden) skiljde sig cellinfiltrationen mellan aseptiska och septiska lossningar, och neutrofiler i ett antal av ≥ 5 celler/högupplösningsfält talade starkt för infektion. Vävnaden kring protesen innehöll celler som behövs, inte bara för ett ospecifikt immunsvar utan också för ett specifikt immunsvar. Detta stödjer hypotesen att de begränsade systemiska inflammatoriska svaret vid höftprotesinfektioner inte beror på att immuncellerna inte förmår ta sig dit, utan troligare beror på att immuncellerna svarar inadekvat på de infekterande bakterierna.

Därför studerade vi vidare samspelet mellan neutrofiler och S. epidermidis (den vanligaste KNS-arten vid höftprotesinfektioner). Neutrofiler hade förmåga att fagocytera (äta upp) både ytbundna och i lösning förekommande S. epidermidis, men ytbundna S. aureus fagocyterades lättare än ytbundna S. epidermidis. Den sämre fagocytosen av S. epidermidis tolkas som en virulensfaktor hos S. epidermidis, tillsammans med frånvaro av förmåga att "prima" eller tillräckligt aktivera neutrofilemas oxidas och genom det undvika avdödning. Den svaga oxidativa aktiveringen stämmer med det låga inflammatoriska svar som ses hos patienter med S. epidermidis infektioner i anslutning till inopererade material. Vidare försenade både S. epidermidis i lösning och adhererade bakterier neutrofilemas apoptos (spontan celldöd), vilket föreslås leda till att neutrofilema samlas på stället för inflammation. Vi föreslår att det komplexa sambandet mellan S. epidermidis-inducerad försenad neutrofildöd och interaktionen mellan S. epidermidis-innehållande neutrofiler och makrofager i vävnaden kring proteser resulterar i en låggradig inflammation, vävnadsskada och slutligen lossning av protesen.

Place, publisher, year, edition, pages
Linköping: Linköping Universitet, 2005. 103 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 902
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-30062 (URN)15522 (Local ID)91-85299-09-X (ISBN)15522 (Archive number)15522 (OAI)
Public defence
2005-06-03, Elsa Brändströmsalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2013-12-11Bibliographically approved

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Nilsdotter-Augustinsson, ÅsaWilsson, ÅsaLarsson, JennyStendahl, OlleÖhman, LenaLundqvist Gustafsson, Helen

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Infectious DiseasesMedical MicrobiologyFaculty of Health SciencesDepartment of Infectious Diseases in ÖstergötlandPathology
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