interleukin-8 and Endocarditis--Bacterial

Staphylococcus aureus is a leading cause of bacteremia, yet there remains a significant knowledge gap in the identification of relevant biomarkers that predict clinical outcomes. Heterogeneity in the host response to invasive S. aureus infection suggests that specific biomarker signatures could be utilized to differentiate patients prone to severe disease, thereby facilitating earlier implementation of more aggressive therapies.. To further elucidate the inflammatory correlates of poor clinical outcomes in patients with S. aureus bacteremia, we evaluated the association between a panel of blood proteins at initial presentation of bacteremia and disease severity outcomes using 2 cohorts of patients with S. aureus bacteremia (n = 32 and n = 124).. We identified 13 candidate proteins that were correlated with mortality and persistent bacteremia. Prognostic modeling identified interleukin (IL)-8 and CCL2 as the strongest individual predictors of mortality, with the combination of these biomarkers classifying fatal outcome with 89% sensitivity and 77% specificity (P < .0001). Baseline IL-17A levels were elevated in patients with persistent bacteremia (P < .0001), endovascular (P = .026) and metastatic tissue infections (P = .012).. These results demonstrate the potential utility of selected biomarkers to distinguish patients with the highest risk for treatment failure and bacteremia-related complications, providing a valuable tool for clinicians in the management of S. aureus bacteremia. Additionally, these biomarkers could identify patients with the greatest potential to benefit from novel therapies in clinical trials.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Biomarkers; Case-Control Studies; Chemokine CCL2; Endocarditis, Bacterial; Female; Humans; Interleukin-17; Interleukin-8; Male; Middle Aged; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Staphylococcal Infections; Staphylococcus aureus; Survival Analysis

Granulicatella and Abiotrophia species are the normal oral flora bacteria that can occasionally cause infective endocarditis. Although substantial data exists in the literature demonstrating occurrence of these species in infective endocarditis, only a few mechanistic studies on their pathogenicity are found. The aim of this study was to investigate the ability of Granulicatella and Abiotrophia species to elicit immune response from human peripheral blood mononuclear cells (PBMC). Biofilms and biofilm supernatants of Granulicatella elegans CCUG 38949, Granulicatella adiacens CCUG 27809 and Abiotrophia defectiva CCUG 27639 were used to stimulate PBMCs for 24 h. Cytokines produced were first screened using a human cytokine membrane array kit. Further, pro-inflammatory cytokines TNF-α, IL-β, and IL-17 were quantified by ELISA. The cytokine profiler array showed the induction of 15 different cytokines/chemokines including IL-1β, IL-6, IL-8, TNF-α, MCP-1, MIP-1α/MIP-1β and RANTES. ELISA quantification revealed that G. adiacens biofilm induced significantly higher (P < 0.05) levels of IL-1β, i.e., 1931 (183) pg/ml than G. elegans or A. defectiva. However, in the case of biofilm supernatants A. defectiva was the strongest, inducing 2104 (574) pg/ml. Biofilm supernatants, but not biofilms from all three species induced TNF-α only weakly. IL-17 was undetectable from any of the stimulated samples. In conclusion, Granulicatella and Abiotrophia are potent inducers of inflammatory mediators from human PBMCs. However, biofilms and biofilm supernatants from these species seem to selectively elicit stimulation of certain cytokines.

Topics: Abiotrophia; Arachidonic Acids; Biofilms; Carnobacteriaceae; Chemokine CCL3; Chemokine CCL4; Chemokines; Cytokines; Endocarditis, Bacterial; Humans; Interleukin-17; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Peptide Fragments; Tumor Necrosis Factor-alpha

The knowledge of systemic inflammation and local cytokine expression in porcine endocarditis models is limited, though it could provide valuable information about the pathogenesis and comparability to human endocarditis. Analyses of bacteriology and hematology were performed on blood samples from pigs with non-bacterial thrombotic endocarditis (NBTE, n = 11), Staphylococcus aureus infective endocarditis (IE, n = 2), animals with S. aureus sepsis without endocarditis (n = 2) and controls (n = 2). Furthermore, immunohistochemistry was used to examine the local expression of IL-1β and IL-8. Bacterial blood cultures were continuously positive in IE pigs from inoculation to euthanasia, and negative in all other pigs at all times. The total white blood cell counts and total neutrophil counts were massively elevated in pigs with IE. Local IL-1β and IL-8 expression in IE pigs were moderate to high, and high, respectively. In addition, slight local expression of IL-1β and IL-8 was present in some NBTE pigs. In the IE model, both the systemic inflammatory response and the high local expression of IL-8 were comparable to the human disease. Furthermore, the results indicate IL-1β and IL-8 as important contributors in the endocarditis pathogenesis.

Topics: Animals; Disease Models, Animal; Endocarditis, Bacterial; Endocarditis, Non-Infective; Female; Humans; Immunohistochemistry; Interleukin-1beta; Interleukin-8; Leukocyte Count; Myocardium; Sepsis; Staphylococcal Infections; Sus scrofa; Systemic Inflammatory Response Syndrome

Surface molecules of Staphylococcus aureus are involved in the colonization of vascular endothelium which is a crucial primary event in the pathogenesis of infective endocarditis (IE). The ability of these molecules to also launch endothelial procoagulant and proinflammatory responses, which characterize IE, is not known. In the present study we investigated the individual capacities of three prominent S. aureus surface molecules; fibronectin-binding protein A (FnBPA) and B (FnBPB) and clumping factor A (ClfA), to promote bacterial adherence to cultured human endothelial cells (ECs) and to activate phenotypic and functional changes in these ECs. Non-invasive surrogate bacterium Lactococcus lactis, which, by gene transfer, expressed staphylococcal FnBPA, FnBPB or ClfA molecules were used. Infection of ECs increased 50- to 100-fold with FnBPA- or FnBPB-positive recombinant lactococci. This coincided with EC activation, interleukin-8 secretion and surface expression of ICAM-1 and VCAM-1 and concomitant monocyte adhesion. Infection with ClfA-positive lactococci did not activate EC. FnBPA-positive L. lactis also induced a prominent tissue factor-dependent endothelial coagulation response that was intensified by cell-bound monocytes. Thus S. aureus FnBPs, but not ClfA, confer invasiveness and pathogenicity to non-pathogenic L. lactis organisms indicating that bacterium-EC interactions mediated by these adhesins are sufficient to evoke inflammation as well as procoagulant activity at infected endovascular sites.

Topics: Adhesins, Bacterial; Bacterial Adhesion; Blood Coagulation; Cell Adhesion; Cells, Cultured; Coagulase; Endocarditis, Bacterial; Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lactococcus lactis; Monocytes; Phenotype; Recombinant Proteins; Staphylococcus aureus; Thromboplastin; Time Factors; Transfection; Vascular Cell Adhesion Molecule-1

The embedding of bacteria in the vegetation of infective endocarditis impedes the penetration of phagocytic cells. IL-8 has a stimulating effect on the immune system, particularly with respect to chemotaxis and activation of granulocytes. Tumor necrosis factor alpha (TNF-alpha) is 1 of the major proinflammatory cytokines. IL-8 and TNF-alpha were visualized by means of immunohistochemistry in paraffin-embedded heart valve biopsies from 6 patients with infective endocarditis who required cardiac surgery during the active phase of the infection. In 5/6 patients there were signs of inflammation, and in these patients IL-8- and TNF-alpha-containing cells were visualized in the heart valve stromas or vegetations. The largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative treatment courses. No such relationships were seen with respect to TNF-alpha-containing cells. These observations may suggest that the occurrence of IL-8-containing cells in infected heart valves could be used as a marker of disease activity.

Topics: Adult; Aged; Bacterial Infections; Biomarkers; Biopsy, Needle; Endocarditis, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Heart Valve Diseases; Heart Valves; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Tumor Necrosis Factor-alpha

Invasion by gram-positive and gram-negative bacterial organisms is characterized immunopathologically by the activation of mononuclear phagocytic cells, leading to the elaboration of macrophage-derived regulatory and chemotactic factors, and the resultant influx of inflammatory leukocytes. Little is known regarding the mechanisms by which gram-positive organisms initiate macrophage activation and subsequent inflammation. In this investigation, we postulated that lipoteichoic acid (LTA) purified from two different gram-positive bacterial species was an important signal for the expression of chemotactic cytokines from human peripheral blood monocytes (PBM). In initial experiments, we demonstrated that cell-associated interleukin-8 (IL-8) was expressed by mononuclear phagocytes present in inflamed areas of endocardium in cases of acute Staphylococcus aureus endocarditis. We next demonstrated that LTA purified from either Staphylococcus aureus or Streptococcus pyogenes induced the time- and dose-dependent expression of IL-8 mRNA and protein from human PBM. The expression of IL-8 mRNA from LTA- but not lipopolysaccharide (LPS)-treated PBM was superinduced by concomitant treatment with cycloheximide, indicating that the expression of IL-8 mRNA from LTA-treated PBM was negatively controlled by repressor proteins. Furthermore, mRNA stability studies indicated that IL-8 mRNA was less stable in the presence of LTA than in the presence of LPS. Our findings indicate that LTA can induce the secretion of the polymorphonuclear leukocyte chemotactic factor IL-8 and that LTA may be an important cellular mediator of inflammatory cell recruitment that characterizes immune responses to gram-positive bacterial infections.

Topics: Cycloheximide; Endocarditis, Bacterial; Gene Expression; Humans; In Vitro Techniques; Interleukin-8; Lipopolysaccharides; Monocytes; RNA, Messenger; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pyogenes; Teichoic Acids