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Biomedical subjects

Anna Norrby-Teglund

Publications and source records attributed to Anna Norrby-Teglund.

At least 19 recordsLinked to original sources
PubMed2006

Streptococcal M protein: a multipotent and powerful inducer of inflammation.

Severe infections with Streptococcus pyogenes, an important human pathogen, are associated with massive inflammatory reactions in the human host. Here we show that streptococcal M protein interacts with TLR2 on human peripheral blood monocytes. As a consequence, monocytes express the cytokines IL-6, IL-1beta, and TNF-alpha. This response is significantly increased in the presence of neutrophil-derived heparin-binding protein (HBP), which co-stimulates monocytes by interacting with CD11/CD18. Analysis of tissue biopsies from patients with necrotizing fasciitis revealed recruitment of neutrophils and monocytes to the infectious site, combined with the release of HBP. The results show that M protein, in synergy with HBP, evokes an inflammatory response that may contribute to the profound pathophysiological consequences seen in severe streptococcal infections.

Animals↗
PubMed2006

Kinin receptor expression during Staphylococcus aureus infection.

An inappropriate host response to invading bacteria is a critical parameter that often aggravates the outcome of an infection. Staphylococcus aureus is a major human Gram-positive pathogen that causes a wide array of community- and hospital-acquired diseases ranging from superficial skin infections to severe conditions such as staphylococcal toxic shock. Here we find that S aureus induces inflammatory reactions by modulating the expression and response of the B1 and B2 receptors, respectively. This process is initiated by a chain of events, involving staphylococcal-induced cytokine release from monocytes, bacteria-triggered contact activation, and conversion of bradykinin to its metabolite desArg(9)bradykinin. The data of the present study implicate an important and previously unknown role for kinin receptor regulation in S aureus infections.

Antigens, Bacterial↗
PubMed2006

Release of SpeA from Streptococcus pyogenes after exposure to penicillin: dependency on dose and inhibition by clindamycin.

The amount and time course of SpeA release from group A streptococci (GAS) was studied at different starting inoculate after exposure to different doses of penicillin, clindamycin or a combination of the 2. The release was related to the bacterial concentration and killing rate. A clinical GAS strain was exposed to benzylpenicillin, 2 and 1000 x MIC, clindamycin, 2 and 32 x MIC, or combinations of the 2. Samples for viable counts and SpeA analyses were drawn before and after the addition of antibiotics and at 3, 6 and 24 h. The SpeA release was higher at low than at high concentrations of penicillin and the combination (both, p<0.05). The addition of clindamycin to penicillin reduced SpeA production at both concentrations (p<0.01). Most SpeA was released before 3 h, and for penicillin and the combination, the amount correlated to the number of killed bacteria during this period (r=0.50; p<0.05). A positive correlation was found between the inoculum size and the SpeA concentration at time zero (r=0.54; p<0.05). The SpeA concentration was dependent on the initial number of bacteria, the class of antibiotic, the dose of penicillin and the killing rate.

Anti-Bacterial Agents↗
PubMed2006

The role of high mobility group box-1 protein in severe sepsis.

PURPOSE OF REVIEW: Despite medical advances, mortality in severe sepsis remains high. As our understanding of the innate immune system has expanded, clinical trials have focused on inhibiting cytokines present early in the infectious process such as interleukin-1 and tumor necrosis factor-alpha, although with disappointing results. There is evidence that the nuclear protein high mobility group box-1 protein, when released extracellularly, acts as a persistent mediator of sepsis and is therefore a promising candidate for therapeutic intervention. This review summarizes current knowledge of the protein and highlights recent relevant findings. RECENT FINDINGS: High mobility group box-1 protein may be released into the circulation either due to necrosis of cells or by active release from macrophages and endothelial cells. Models of experimental sepsis in mice have shown a strong association between extracellular high mobility group box-1 protein and lethality. Treatments against the biological activities of high mobility group box-1 protein reduce lethality in these models. Other studies have shown high mobility group box-1 protein as a key regulator in acute and chronic inflammation. Recent findings confirm that high mobility group box-1 protein is persistently elevated in human patients with severe sepsis. SUMMARY: Despite all efforts, mortality in severe sepsis remains high. A massive amount of evidence indicates high mobility group box-1 protein as a delayed and important propagator of inflammation. Recent studies confirm persisting high levels of high mobility group box-1 protein in serum up to 1 week after hospitalization. Reducing levels of the protein by anti-high mobility group box-1 protein treatment may be one way to moderate uncontrolled inflammation seen in sepsis.

Animals↗
PubMed2006

Viable group A streptococci in macrophages during acute soft tissue infection.

BACKGROUND: Group A streptococcal severe soft tissue infections, such as necrotizing fasciitis, are rapidly progressive infections associated with high mortality. Group A streptococcus is typically considered an extracellular pathogen, but has been shown to reside intracellularly in host cells. METHODS AND FINDINGS: We characterized in vivo interactions between group A streptococci (GAS) and cells involved in innate immune responses, using human biopsies (n = 70) collected from 17 patients with soft tissue infections. Immunostaining and in situ image analysis revealed high amounts of bacteria in the biopsies, even in those collected after prolonged antibiotic therapy. Viability of the streptococci was assessed by use of a bacterial viability stain, which demonstrated viable bacteria in 74% of the biopsies. GAS were present both extracellularly and intracellularly within phagocytic cells, primarily within macrophages. Intracellular GAS were predominantly noted in biopsies from newly involved tissue characterized by lower inflammation and bacterial load, whereas purely extracellular GAS or a combination of intra- and extracellular GAS dominated in severely inflamed tissue. The latter tissue was also associated with a significantly increased amount of the cysteine protease streptococcal pyrogenic exotoxin SpeB. In vitro studies confirmed that macrophages serve as reservoirs for viable GAS, and infection with a speB-deletion mutant produced significantly lower frequencies of cells with viable GAS following infection as compared to the wild-type bacteria. CONCLUSIONS: This is the first study to demonstrate that GAS survive intracellularly in macrophages during acute invasive infections. This intracellular presence may have evolved as a mechanism to avoid antibiotic eradication, which may explain our finding that high bacterial load is present even in tissue collected after prolonged intravenous antibiotic therapy. This new insight into the pathogenesis of streptococcal soft tissue infections highlights a need for alternative therapeutic strategies.

Bacterial Proteins↗
PubMed2005

Dual effects of extracellular adherence protein from Staphylococcus aureus on peripheral blood mononuclear cells.

Extracellular adherence protein (Eap) has been suggested as an important virulence factor of Staphylococcus aureus because it enhances bacterial adherence and internalization into eukaryotic cells, interference with T cells, and neutrophil adherence to endothelial cells. We demonstrate that Eap has dual effects on peripheral blood mononuclear cells, depending on its concentration. At low concentrations (up to 9 microg/mL), Eap induces a proliferative response; at higher concentrations, it causes a significant inhibition of T cell proliferation induced by S. aureus supernatants toxic shock syndrome toxin-1 or phytohemagglutinin. A marked increase in apoptotic (i.e., Annexin V and propidium iodide positive) T and B cells could be demonstrated after exposure to the inhibitory concentration of Eap. Human anti-Eap antibodies prepared from polyspecific immunoglobulin G (IgG) blocked the immunomodulatory effects of Eap. Our results demonstrate novel immunomodulatory activities of Eap and identify potential mechanisms of action of intravenous IgG therapy in the treatment of S. aureus infections.

Bacterial Proteins↗
PubMed2005

Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock.

OBJECTIVE: To study the systemic release and kinetics of high mobility group box-1 protein (HMGB1) in relation to clinical features in a population of patients with severe sepsis or septic shock and to compare these with the kinetics of the cytokines interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha. DESIGN: Prospective study of two cohorts of patients. SETTING: Intensive care unit and infectious disease clinic at Karolinska University Hospital Huddinge. PATIENTS: Twenty-six patients with severe sepsis, 33 patients with septic shock, and a reference group of five patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-four patients were included, ten of whom died within 28 days. Cytokine levels were measured at five time points during the first week after admission and were correlated to Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Two HMGB1 assays were used. Both demonstrated delayed kinetics for HMGB1 with high levels on inclusion that remained high throughout the study period. Serum concentration at 144 hrs, the last sampling point, was 300 times higher, 34,000 +/- 76,000 pg/mL (mean +/- sd), than any of the other cytokines. This study, however, found no predictable correlation between serum levels of HMGB1 and severity of infection. We did quite unexpectedly find significantly lower levels of HMGB1 in nonsurvivors compared with survivors as measured by our main assay, but the other showed no difference between the two groups. Levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha correlated significantly with severity of disease, and all were significantly higher in patients with septic shock compared with those with severe sepsis. Neither of these comparisons showed significant correlations for HMGB1. CONCLUSIONS: This is the first prospective study assessing the release over time of HMGB1 in a population of patients with sepsis, severe sepsis, or septic shock. Levels remained high in the majority of patients up to 1 wk after admittance, indicating that the cytokine indeed is a downstream and late mediator of inflammation. Further studies are required to fully define the relationship of HMGB1 to severity of disease.

Biomarkers↗
PubMed2005

Variations in emm type among group A streptococcal isolates causing invasive or noninvasive infections in a nationwide study.

Since the late 1980s several studies have described the increased incidence and severity of invasive group A streptococcal (GAS) infections. However, most studies on GAS pathogenesis have focused on information obtained during outbreaks. We analyzed isolate distribution and host susceptibility as part of a nationwide prospective surveillance study performed between January 2001 and August 2002. GAS isolates collected from 201 patients with invasive infections, 335 patients with noninvasive infections, and 17 asymptomatic carriers were characterized with respect to their emm types and superantigen genotypes. The superantigen-neutralizing capacity and levels of antibodies against streptolysin O and DNAse B were determined for isolates from the sera from 36 invasive cases and 91 noninvasive cases. emm type 1 (emm-1) isolates were significantly more common among invasive cases, whereas emm-4, emm-6, and emm-12 dominated among the noninvasive cases. The distributions of the phage-associated superantigen genes (speA, speC, speH, speI, ssa) differed among invasive and noninvasive isolates, mainly due to their linkage to certain emm types. No significant differences in serum superantigen-neutralizing capacities were observed. The levels of anti-streptolysin O and anti-DNAse B antibodies were highest in the sera from invasive cases. Our study emphasizes the importance of obtaining data during years with stable incidences, which will enable evaluation of future outbreak data.

Adolescent↗
PubMed2004

Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome.

Administration of intravenous polyspecific immunoglobulin G (IVIG) has been proposed as adjunctive therapy for toxic shock syndrome caused by Streptococcus pyogenes or Staphylococcus aureus. We investigated whether superantigen-containing culture supernatants prepared from streptococcal isolates (n=21) and staphylococcal isolates (n=20) from cases of severe sepsis were inhibited to an equal extent by IVIG in proliferation experiments that used human peripheral blood mononuclear cells. All 3 IVIG preparations tested were highly efficient in neutralizing the superantigens, and most supernatants were completely inhibited at concentrations ranging from 0.05 to 2.5 mg IVIG/mL. An important finding was that culture supernatants from S. pyogenes isolates were consistently inhibited to a greater extent than those of S. aureus isolates (P<.01). The findings demonstrate that staphylococcal superantigens are not inhibited as efficiently as streptococcal superantigens by IVIG, and, hence, a higher dose of IVIG may be required for therapy of staphylococcal toxic shock syndrome in order to achieve protective titers and clinical efficacy.

Humans↗
PubMed2004

M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage.

Increased vascular permeability is a key feature of inflammatory conditions. In severe infections, leakage of plasma from the vasculature induces a life-threatening hypotension. Streptococcus pyogenes, a major human bacterial pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma leakage and multi-organ failure. Here we find that M protein, released from the streptococcal surface, forms complexes with fibrinogen, which by binding to beta2 integrins of neutrophils, activate these cells. As a result, neutrophils release heparin binding protein, an inflammatory mediator inducing vascular leakage. In mice, injection of M protein or subcutaneous infection with S. pyogenes causes severe pulmonary damage characterized by leakage of plasma and blood cells. These lesions were prevented by treatment with a beta2 integrin antagonist. In addition, M protein/fibrinogen complexes were identified in tissue biopsies from a patient with necrotizing fasciitis and STSS, further underlining the pathogenic significance of such complexes in severe streptococcal infections.

Animals↗
PubMed2004

Clinical significance of untreated Candida species isolated from ascites in cirrhotic patients.

The clinical significance of Candida species isolated from cirrhotic ascites is still unknown. We reviewed the clinical and laboratory features of all cirrhotic patients whose ascites samples were positive for Candida species. A total of 21 cirrhotic patients was identified. Patients were regarded as having peritonitis if they had 1 or more clinical symptom(s) or sign(s) in the absence of any other possible explanation. 10 patients (47.6%) were classified into the spontaneous Candida peritonitis (SCP) group, and the remaining 11 patients (52.4%) were classified into asymptomatic candidascites. Mortalities were higher in the SCP group at discharge (50.0% vs 27.3%), 6-month (90% vs 45.5%) and 1-y (100% vs 54.5%) (p=0.007). Receiver-operating characteristic curve analysis revealed that the cut-off value of ascitic fluid polymorphonuclear cell count of 315/mm(3) (0.315 x 10(9)/l) had the highest diagnostic accuracy with both sensitivity and specificity of 1.0. In conclusion, Candida species are associated with a grave outcome when manifested with peritonitis.

Adult↗
PubMed2004

Rectal nitric oxide gas and stool cytokine levels during the course of infectious gastroenteritis.

Nitric oxide (NO) is known to be an important inflammatory mediator with a potential role in gastrointestinal diseases. We prospectively studied the luminal NO levels in 51 patients with infectious gastroenteritis, 35 patients with nonenteric bacterial infections, and 11 healthy control subjects. The levels of proinflammatory cytokines were simultaneously measured in the stools of patients with gastroenteritis. Rectal gas was sampled with balloon catheters made of silicone and was analyzed for NO levels by chemiluminescence. The median rectal NO level was 2,450 ppb in the acute phase of gastroenteritis and gradually decreased to 225 ppb after 3 to 8 weeks, whereas the median NO values were 150 ppb in patients with nonenteric bacterial infections and 100 ppb in healthy control subjects. Patients with Salmonella, Shigella, and Campylobacter infections generally had more severe symptoms and a higher median NO level (17,250 ppb) than patients with Clostridium difficile-associated diarrhea (median NO value, 275 ppb). Interleukin-1 beta levels were elevated in 82% of the patients at disease onset and decreased during the convalescent phase. In contrast, gamma interferon was detected in only 16% of the patients and was predominantly collected in stool samples collected during the subacute and convalescent stages. Our data point to the possibility of using this easy, minimally invasive method for luminal NO measurement as a diagnostic tool, among others, to evaluate the degree of intestinal inflammation in patients with infectious gastroenteritis.

Adult↗
PubMed2003

Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial.

The efficacy and safety of high-dose intravenous polyspecific immunoglobulin G (IVIG) as adjunctive therapy in streptococcal toxic shock syndrome (STSS) were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The trial was prematurely terminated because of slow patient recruitment, and results were obtained from 21 enrolled patients (10 IVIG recipients and 11 placebo recipients). The primary end point was mortality at 28 days, and a 3.6-fold higher mortality rate was found in the placebo group. A significant decrease in the sepsis-related organ failure assessment score at days 2 (P=.02) and 3 (P=.04) was noted in the IVIG group. Furthermore, a significant increase in plasma neutralizing activity against superantigens expressed by autologous isolates was noted in the IVIG group after treatment (P=.03). Although statistical significance was not reached in the primary end point, the trial provides further support for IVIG as an efficacious adjunctive therapy in STSS.

Adult↗
PubMed2003

The Treatment of Severe Group A Streptococcal Infections.

Group A streptococci can cause a variety of diseases ranging from uncomplicated superficial infections to severe systemic infections associated with high morbidity and mortality. Since the late 1980s a drastic resurgence of highly aggressive invasive streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have been noted worldwide. This has prompted intense research in the field and important new information has been gained regarding the pathogenesis and treatment of life-threatening invasive group A streptococcal infections. Exotoxins with superantigenic activities have been identified as central mediators of the systemic effects seen in streptococcal toxic shock syndrome. Novel therapeutic strategies include agents that can inhibit these superantigens, and one promising candidate is intravenous polyspecific immunoglobulin that contains neutralizing antibodies against a wide spectrum of streptococcal superantigens. Intravenous immunoglobulin adjunctive therapy was shown in a case-control study to reduce mortality in patients with streptococcal toxic shock syndrome.

Journal Article↗
PubMed2003

Intravenous immunoglobulin adjunctive therapy in sepsis, with special emphasis on severe invasive group A streptococcal infections.

Immunotherapy targeted against microbial toxins and host mediators has been studied in many preclinical investigations and clinical trials of sepsis during the past 20 y. Intravenous immunoglobulin, including both monoclonal and polyclonal antibodies, represents one such immunotherapeutic strategy. Mononclonal antibodies directed against endotoxin or tumour necrosis factor-alpha have been tested extensively in clinical trials, but have so far failed to reveal a significant effect on mortality rates. Several studies have assessed the efficacy of polyclonal intravenous immunoglobulin (IVIG) in sepsis, with varying results. Although there are no conclusive data available to date to support the use of IVIG therapy in all sepsis cases, there are strong indications that certain defined septic subgroups, such as streptococcal toxic shock syndrome caused by group A streptococcus, will benefit from its use. This review briefly summarizes the clinical trials on IVIG therapy in sepsis, and describes in more detail the mechanistic actions of IVIG and the clinical data that support the use of IVIG as adjunctive therapy in severe invasive group A streptococcal infections.

Humans↗
PubMed2003

Extracellular adherence protein from Staphylococcus aureus enhances internalization into eukaryotic cells.

In this study we have shown that Eap (extracellular adherence protein) plays a role in the internalization process of Staphylococcus aureus into eukaryotic cells. Eap is a protein that is mostly extracellularly and to a lesser extent is bound to the bacterial surface as a result of rebinding. Eap is able to bind to several plasma proteins, such as fibronectin, fibrinogen, and prothrombin. It has the capacity to form oligomers and is able to agglutinate S. aureus. A mutant strain, Newman mAH12 (eap:: Ery(r)), with a deficient eap gene was used in the present study. We have demonstrated that (i) strain Newman mAH12 could adhere to and become internalized to a higher extent by eukaryotic cells than the isogenic mutant, (ii) strain Newman mAH12 complemented with the eap gene displayed restoration of the internalization level, (iii) externally added Eap enhanced the internalization of laboratory and clinical S. aureus strains as well as of S. carnosus (a coagulase-negative species devoid of proteins important for internalization), and (iv) antibodies against Eap were able to block the internalization process in strain Newman mAH12 and clinical isolates. Eap, with its broad binding capacity and its surface localization, thus seems to contribute to the internalization of S. aureus into eukaryotic cells. We therefore propose a novel internalization pathway for S. aureus in which Eap plays an enhancing role.

Adhesins, Bacterial↗
PubMed2002

An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.

The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

Fasciitis, Necrotizing↗