| 1. |
- Abdillahi, Suado M, et al.
(författare)
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The Pulmonary Extracellular Matrix Is a Bactericidal Barrier Against Haemophilus influenzae in Chronic Obstructive Pulmonary Disease (COPD) : Implications for an in vivo Innate Host Defense Function of Collagen VI
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Non-typeable Haemophilus influenzae (NTHi) is a Gram-negative human commensal commonly residing in the nasopharynx of preschool children. It occasionally causes upper respiratory tract infection such as acute otitis media, but can also spread to the lower respiratory tract causing bronchitis and pneumonia. There is increasing recognition that NTHi has an important role in chronic lower respiratory tract inflammation, particularly in persistent infection in patients suffering from chronic obstructive pulmonary disease (COPD). Here, we set out to assess the innate protective effects of collagen VI, a ubiquitous extracellular matrix component, against NTHi infection in vivo. In vitro, collagen VI rapidly kills bacteria through pore formation and membrane rupture, followed by exudation of intracellular content. This effect is mediated by specific binding of the von Willebrand A (VWA) domains of collagen VI to the NTHi surface adhesins protein E (PE) and Haemophilus autotransporter protein (Hap). Similar observations were made in vivo specimens from murine airways and COPD patient biopsies. NTHi bacteria adhered to collagen fibrils in the airway mucosa and were rapidly killed by membrane destabilization. The significance in host-pathogen interplay of one of these molecules, PE, was highlighted by the observation that it confers partial protection from bacterial killing. Bacteria lacking PE were more prone to antimicrobial activity than NTHi expressing PE. Altogether the data shed new light on the carefully orchestrated molecular events of the host-pathogen interplay in COPD and emphasize the importance of the extracellular matrix as a novel branch of innate host defense.
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| 2. |
- Agarwal, Vaibhav, et al.
(författare)
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An Alternative Role of C1q in Bacterial Infections: Facilitating Streptococcus pneumoniae Adherence and Invasion of Host Cells.
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 191:8, s. 4235-4245
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae (pneumococcus) is a major human pathogen, which evolved numerous successful strategies to colonize the host. In this study, we report a novel mechanism of pneumococcal-host interaction, whereby pneumococci use a host complement protein C1q, primarily involved in the host-defense mechanism, for colonization and subsequent dissemination. Using cell-culture infection assays and confocal microscopy, we observed that pneumococcal surface-bound C1q significantly enhanced pneumococcal adherence to and invasion of host epithelial and endothelial cells. Flow cytometry demonstrated a direct, Ab-independent binding of purified C1q to various clinical isolates of pneumococci. This interaction was seemingly capsule serotype independent and mediated by the bacterial surface-exposed proteins, as pretreatment of pneumococci with pronase E but not sodium periodate significantly reduced C1q binding. Moreover, similar binding was observed using C1 complex as the source of C1q. Furthermore, our data show that C1q bound to the pneumococcal surface through the globular heads and with the host cell-surface receptor(s)/glycosaminoglycans via its N-terminal collagen-like stalk, as the presence of C1q N-terminal fragment and low m.w. heparin but not the C-terminal globular heads blocked C1q-mediated pneumococcal adherence to host cells. Taken together, we demonstrate for the first time, to our knowledge, a unique function of complement protein C1q, as a molecular bridge between pneumococci and the host, which promotes bacterial cellular adherence and invasion. Nevertheless, in some conditions, this mechanism could be also beneficial for the host as it may result in uptake and clearance of the bacteria.
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| 3. |
- Agarwal, Vaibhav, et al.
(författare)
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Binding of Streptococcus pneumoniae endopeptidase O (PepO) to complement component C1q modulates the complement attack and promotes host cell adherence.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:22, s. 15833-15844
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Tidskriftsartikel (refereegranskat)abstract
- The Gram-positive species Streptococcus pneumoniae is a human pathogen causing severe local and life-threatening invasive diseases associated with high mortality rates and death. We demonstrated recently that pneumococcal endopeptidase O (PepO) is an ubiquitously expressed, multifunctional plasminogen and fibronectin binding protein facilitating host cell invasion and evasion of innate immunity. In this study we found that PepO interacts directly with the complement C1q protein, thereby attenuating the classical complement pathway and facilitating pneumococcal complement escape. PepO binds both free C1q and C1 complex in a dose-dependent manner based on ionic interactions. Our results indicate that recombinant PepO specifically inhibits the classical pathway of complement activation in both hemolytic and complement deposition assays. This inhibition is due to direct interaction of PepO with C1q, leading to a strong activation of the classical complement pathway and results in consumption of complement components. In addition, PepO binds the classical complement pathway inhibitor C4BP, thereby regulating downstream complement activation. Importantly, pneumococcal surface-exposed PepO-C1q interaction mediates bacterial adherence to host epithelial cells. Taken together, PepO facilitates C1q-mediated bacterial adherence, while its localized release consumes complement as a result of its activation following binding of C1q, thus representing an additional mechanism of human complement escape by this versatile pathogen.
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| 4. |
- Agarwal, Vaibhav, et al.
(författare)
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Enolase of Streptococcus pneumoniae Binds Human Complement Inhibitor C4b-Binding Protein and Contributes to Complement Evasion.
- 2012
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 189:7, s. 3575-3584
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae (pneumococcus) is a pathogen that causes severe local and life-threatening invasive diseases, which are associated with high mortality rates. Pneumococci have evolved several strategies to evade the host immune system, including complement to disseminate and to survive in various host niches. Thus, pneumococci bind complement inhibitors such as C4b-binding protein (C4BP) and factor H via pneumococcal surface protein C, thereby inhibiting the classical and alternative complement pathways. In this study, we identified the pneumococcal glycolytic enzyme enolase, a nonclassical cell surface and plasminogen-binding protein, as an additional pneumococcal C4BP-binding protein. Furthermore, we demonstrated that human, but not mouse, C4BP bound pneumococci. Recombinant enolase bound in a dose-dependent manner C4BP purified from plasma, and the interaction was reduced by increasing ionic strength. Enolase recruited C4BP and plasminogen, but not factor H, from human serum. Moreover, C4BP and plasminogen bound to different domains of enolase as they did not compete for the interaction with enolase. In direct binding assays with recombinant C4BP mutants lacking individual domains, two binding sites for enolase were identified on the complement control protein (CCP) domain 1/CCP2 and CCP8 of the C4BP α-chains. C4BP bound to the enolase retained its cofactor activity as determined by C4b degradation. Furthermore, in the presence of exogenously added enolase, an increased C4BP binding to and subsequently decreased C3b deposition on pneumococci was observed. Taken together, pneumococci specifically interact with human C4BP via enolase, which represents an additional mechanism of human complement control by this versatile pathogen.
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| 5. |
- Agarwal, Vaibhav, et al.
(författare)
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Streptococcus pneumoniae endopeptidase O (PepO): a multifunctional plasminogen and fibronectin binding protein, facilitating evasion of innate immunity and invasion of host cells.
- 2013
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 288:10, s. 6849-6863
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. Therefore a detailed understanding and characterization of the mechanism of host cell colonization and dissemination is critical in order to gain control over this versatile pathogen. Here we identified a novel 72 kDa pneumococcal protein endopeptidase O (PepO), as a plasminogen and fibronectin binding protein. Using a collection of clinical isolates, representing different serotypes, we found PepO to be ubiquitously present both at the gene and at the protein level. In addition, PepO protein was secreted in a growth-phase dependent manner to the culture supernatants of the pneumococcal isolates. Recombinant PepO bound human plasminogen and fibronectin in a dose-dependent manner and plasminogen did not compete with fibronectin for binding PepO. PepO bound plasminogen via lysine residues and the interaction was influenced by ionic strength. Moreover, upon activation of PepO bound plasminogen by urokinase-type plasminogen activator, generated plasmin cleaved complement protein C3b thus assisting in complement control. Furthermore, direct binding assays demonstrated the interaction of PepO with epithelial and endothelial cells that in turn blocked pneumococcal adherence. Moreover, a pepO-mutant strain showed impaired adherence to and invasion of host cells compared to their isogenic wild-type strains. Taken together, the results demonstrated that PepO is ubiquitously expressed plasminogen and fibronectin binding protein, which plays role in pneumococcal invasion of host cells and aids in immune evasion.
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| 6. |
- Ahl, Jonas, et al.
(författare)
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High incidence of septic shock caused by Streptococcus pneumoniae serotype 3-a retrospective epidemiological study
- 2013
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Ingår i: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: More than 90 immunologically distinct serotypes of Streptococcus pneumoniae exist, and it is not fully elucidated whether the serotype is a risk factor for severity of invasive pneumococcal disease (IPD). Our hypothesis is that serotypes differ in their capacity to cause septic shock. Methods: We performed a retrospective study in Southern Sweden based upon 513 patients with IPD in the pre-vaccine era 2006-2008. The serotype, co-morbidity, and sepsis severity were determined. Serotypes were compared to serotype 14 as a reference and grouped according to their invasive potential, that is, high (serogroups 1, 5 and 7), intermediate (serogroups 4, 9, 14 and 18) and, finally, low invasive potential (serogroups 3, 6, 8, 15, 19, 23 and 33). Results: Patients with S. pneumoniae serotype 3 had significantly more often septic shock (25%, odds ratio (OR) 6.33 [95% confidence interval (CI) 1.59-25.29]), higher mortality (30%, OR 2.86 [CI 1.02-8.00]), and more often co-morbidities (83%, OR 3.82 [CI 1.39-10.54]) when compared to serotype 14. A significant difference in age and co-morbidities (p= 0.001) was found when patient data were pooled according to the invasive potential of the infecting pneumococci. The median age and percentage of patients with underlying co-morbidities were 72 years and 79%, respectively, for serogroups associated with low invasiveness, 68 years and 61%, respectively, for serogroups with intermediate invasiveness, and, finally, 62 years and 48%, respectively, for serogroups with high invasiveness. No difference in sepsis severity was found between the three groups. Conclusions: S. pneumoniae serotype 3 more often caused septic shock compared to serotype 14. Our results support the hypothesis that serotypes with high invasiveness mainly cause IPD in younger patients with less co-morbidities. In contrast, serogroups with low and intermediate invasive potential mostly cause IPD in the elderly with defined co-morbidities, and thus can be considered as opportunistic.
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| 7. |
- Ahl, Jonas, et al.
(författare)
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Prevalence of penicillin-non-susceptible Streptococcus pneumoniae in children in day-care centres subjected to an intervention to prevent dispersion.
- 2015
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Ingår i: Infectious Diseases. - : Informa UK Limited. - 2374-4243 .- 2374-4235. ; 47:5, s. 338-344
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to evaluate the day-care interventions implemented in southern Sweden to restrict the dispersion of penicillin-non-susceptible pneumococci with a minimum inhibitory concentration of penicillin G of at least 0.5 mg/l (PNSP0.5). Methods: A retrospective epidemiological study was performed and data from 109 day-care centre interventions from 2000 to 2010 were analysed, including screening results from 7157 individuals. Results: It was found that 42% of the children were carriers of pneumococci and 5% of the screened children were PNSP0.5 carriers. Very few personnel were PNSP0.5 carriers and they were carriers for only a short time. Significantly more contact cases with the same serogroup as the index case were found in the first screening and in the same department as the index case, but a substantial number of contact cases were found in adjacent departments. Conclusions: Screening of personnel is not worth the effort. Based on our results, procedures to restrict dispersion of PNSP0.5 in day-care centres could be improved. To find the majority of contact cases with PNSP0.5 an early screening including adjacent departments seems to be the best approach.
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| 8. |
- Ahl, Jonas, et al.
(författare)
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Risk Factors for Pneumococcal Carriage in Day Care Centers: A Retrospective Study During a 10-year Period.
- 2014
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Ingår i: Pediatric Infectious Disease Journal. - 1532-0987. ; 33:5, s. 536-538
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Tidskriftsartikel (refereegranskat)abstract
- In this retrospective epidemiologic study, we present pneumococcal carriage data from 109 Swedish day care centers over a period of 10 years. Aspects of season, age, personnel and group size were studied. We found a significant seasonal variation in pneumococcal carriage. Group size was a significant risk factor for pneumococcal carriage. Pneumococcal carriage was 4.5 % in personnel.
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| 9. |
- Ahrén, Irini Lazou, et al.
(författare)
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The importance of a β-glucan receptor in the nonopsonic entry of nontypeable Haemophilus influenzae into human monocytic and epithelial cells
- 2001
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 184:2, s. 150-158
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Tidskriftsartikel (refereegranskat)abstract
- Previous reports showed that nontypeable Haemophilus influenzae (NTHi) reside in macrophage-like cells in human adenoid tissue. This study investigated the ability of nonopsonized NTHi and encapsulated H. influenzae type b (Hib) to enter human monocytic and epithelial cells. The number of intracellular bacteria was determined by a viability assay and flow cytometry. To characterize the mechanisms responsible for the internalization of NTHi, different inhibitors of surface molecules, receptor turnover, and the cytoskeleton were used. Hib were found in monocytic cells at very low numbers (<100 bacteria/2 × 105 cells). In contrast, a great variation in intracellular numbers was detected between the different NTHi isolates (range, 0.0007%-0.28% of the inoculum for monocytes and 0.053%-3.5% for epithelial cells). NTHi entered human monocytic and epithelial cells via a receptor-mediated endocytosis involving mainly a β-glucan receptor that could be blocked by laminarin.
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| 10. |
- Ahren, IL, et al.
(författare)
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Nontypeable Haemophilus influenzae activates human eosinophils through beta-glucan receptors
- 2003
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 29:5, s. 598-605
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils are a characteristic component of the inflammatory response seen in several diseases, including allergic asthma and chronic obstructive pulmonary disease. After activation, eosinophil-derived products may exert proinflammatory effects and cause considerable tissue damage. In the present study, we investigated innate interactions between the respiratory tract pathogen nontypeable Haemophilus influenzae (NTHi) and human eosinophils. Bacterial binding to eosinophils was dependent on (1-3)-beta-D-glucan receptors, as deduced from blocking experiments using the soluble glucan derivatives laminarin and scleroglucan. In addition, expression of the beta-glucan receptor dectin-1 was shown in eosinophils by reverse transcriptase-polymerase chain reaction. Activation of the beta-glucan receptors by bacteria elicited a time- and dose-dependent respiratory burst in eosinophils. NTHi caused increased expression of the proinflammatory chemokine interleukin-8 as measured by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Incubation of eosinophils in the presence of NTHi for 4.5 h revealed upregulation of 245 different genes as detected by microarray. Signal transduction-related transcripts were most strongly upregulated, followed by cytokine mRNAs. Our findings suggest that NTHi can induce an innate inflammatory response in eosinophils that is mainly mediated via beta-glucan receptors. This points to possible pathophysiologic mechanisms involving innate recognition of NTHi by eosinophils during infection of the airways, thus promoting inflammation in chronic pulmonary disease.
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