| 1. |
- Beiter, Katharina, et al.
(författare)
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An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps
- 2006
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Ingår i: Current Biology. - : Elsevier BV. - 1879-0445 .- 0960-9822. ; 16:4, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia, with high morbidity and mortality worldwide. A major feature of pneumococcal pneumonia is an abundant neutrophil infiltration . It was recently shown that activated neutrophils release neutrophil extracellular traps (NETs), which contain antimicrobial proteins bound to a DNA scaffold. NETs provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly. Here, we show that pneumococci are trapped but, unlike many other pathogens, not killed by NETs. NET trapping in the lungs, however, may allow the host to confine the infection, reducing the likelihood for the pathogen to spread into the bloodstream. DNases are expressed by many Gram-positive bacterial pathogens, but their role in virulence is not clear. Expression of a surface endonuclease encoded by endA is a common feature of many pneumococcal strains. We show that EndA allows pneumococci to degrade the DNA scaffold of NETs and escape. Furthermore, we demonstrate that escaping NETs promotes spreading of pneumococci from the upper airways to the lungs and from the lungs into the bloodstream during pneumonia.
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| 2. |
- Littmann, Marie, et al.
(författare)
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Streptococcus pneumoniae evades human dendritic cell surveillance by pneumolysin expression
- 2009
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 1:4, s. 211-222
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) protect the respiratory epithelium via induction of innate immune responses and priming of naive T cells during the initiation of adaptive immunity. Streptococcus pneumoniae, a commonly carried asymptomatic member of the human nasopharyngeal microflora, can cause invasive and inflammatory diseases and the cholesterol-dependent cytotoxin pneumolysin is a major pneumococcal virulence factor implicated in compounding tissue damage and mediating inflammatory responses. While most studies examining the impact of pneumolysin have been based on murine models, we have focused this study on human DC responses. We show that expression of haemolytic pneumolysin inhibits human DC maturation, induction of proinflammatory cytokines and activation of the inflammasome. Furthermore, intracellular production of pneumolysin induces caspase-dependent apoptosis in infected DCs. Similarly, clinical isolates with non-haemolytic pneumolysin were more proinflammatory and caused less apoptosis compared to clonally related strains with active pneumolysin. This study describes a novel role of pneumolysin in the evasion of human DC surveillance that could have a profound clinical impact upon inflammatory disease progression and highlights the need to study human responses to human-specific pathogens.
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| 3. |
- Muschiol, Sandra, et al.
(författare)
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A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
- 2006
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Ingår i: National Academy of Sciences, USA. - Washington : Proceedings of the National Academy of Sciences. ; , s. 14566-71
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.
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| 4. |
- Parihar, Vishal Singh, et al.
(författare)
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Characterization of human invasive isolates of Listeria monocytogenes in Sweden 1986-2007
- 2008
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Ingår i: Foodborne pathogens and disease. - : Mary Ann Liebert. - 1535-3141 .- 1556-7125. ; 5:6, s. 755-761
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Tidskriftsartikel (refereegranskat)abstract
- Since 1986, 68% of the Listeria monocytogenes isolates from human cases of invasive listeriosis in Sweden are available for retrospective studies. The aim of the present study was to characterize 601 human invasive isolates of L. monocytogenes in Sweden from 1986 to 2007 by using serotyping and pulsed-field gel electrophoresis. Since 1996, serovar 4b was permanently reduced to the second or third most common serovar in human cases in Sweden. During the latter period, 2000-2007, only 13% belonged to serovar 4b and 71% to 1/2a. The dendrogram, based on pulsovars, reveals two clusters with different serovars. Cluster 1 exhibits serovars 4b and 1/2b, whereas cluster 2 consists of serovar 1/2a. Serovar 1/2a seems to be more heterogeneous than serovar 4b.
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| 5. |
- Bailey, Leslie, et al.
(författare)
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Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
- 2007
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Ingår i: FEBS Letters. - : Elsevier. - 0014-5793 .- 1873-3468. ; 581:4, s. 587-595
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Tidskriftsartikel (refereegranskat)abstract
- Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.
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| 6. |
- Darenberg, Jessica, et al.
(författare)
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Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden
- 2007
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1537-6591 .- 1058-4838. ; 45:4, s. 8-450
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Tidskriftsartikel (refereegranskat)abstract
- Background. The incidence and severity of invasive group A streptococcal infection demonstrate great variability over time, which at least, in part, seems to be related to group A streptococcal type distribution among the human population. Methods. An enhanced surveillance study of invasive group A streptococcal infection (746 isolates) was performed in Sweden from April 2002 through December 2004. Noninvasive isolates from either the throat or skin (773 isolates) were collected in parallel for comparison. Clinical and epidemiological data were obtained from 88% of patients with invasive disease and were related to isolate characteristics, including T type, emm sequence type, and the presence of 9 superantigen genes, as well as pulsed-field gel electrophoresis pattern comparisons of selected isolates. Results. The annual incidence was 3.0 cases per 100,000 population. Among the patients with invasive disease, 11% developed streptococcal toxic shock syndrome, and 9.5% developed necrotizing fasciitis. The overall case-fatality rate was 14.5%, and 39% of the patients with streptococcal toxic shock syndrome died (P < .001). The T3/13/B3264 cluster accounted for 33% of invasive and 25% of noninvasive isolates. Among this most prevalent type cluster, emm types 89 and 81 dominated. Combined results from pulsed-field gel electrophoresis, emm typing, and superantigen gene profiling identified subgroups within specific emm types that are significantly more prone to cause invasive disease than were other isolates of the same type. Conclusions. This study revealed a changing epidemiology of invasive group A streptococcal infection in Sweden, with emergence of new emm types that were previously not described. The results also suggest that some clones may be particularly prone to cause invasive disease.
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| 7. |
- Dieudonné-Vatran, Antoine, et al.
(författare)
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Clinical isolates of Streptococcus pneumoniae bind the complement inhibitor C4b-binding protein in a PspC allele-dependent fashion.
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:12, s. 7865-7877
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Tidskriftsartikel (refereegranskat)abstract
- The complement system constitutes an important component of the innate immune system. To colonize their host and/or to cause disease, many pathogens have evolved strategies to avoid complement-mediated bacterial lysis and opsonophagocytosis. In this study, using a collection of 55 clinical isolates of Streptococcus pneumoniae, we demonstrate for the first time that pneumococci bind the complement inhibitor C4b-binding protein (C4BP). C4BP binding seems to be restricted to certain serotypes such as serotype 4, 6B, 7F, and 14, of which the strains of serotype 14 are the strongest binders. We show that bacteria-bound C4BP retains its functional activity and down-regulates the activation of the classical pathway. Thus, this major respiratory pathogen may escape immune recognition and eradication by the complement system. Furthermore, we show that C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4. The study of the distribution of group 4 pspC locus shows that most of high-binder serotype 14 isolates harbor an allelic variant of group 4 pspC. Using PspC-negative mutant strains, we identified a new allelic variant of PspC (PspC4.4) as a major ligand for C4BP, revealing a new function for this important pneumococcal virulence factor. Thus pneumococci exploit host C4BP for complement evasion in a PspC allele-dependent manner.
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| 8. |
- Karlsson, Diana, et al.
(författare)
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An individual-based network model to evaluate interventions for controlling pneumococcal transmission
- 2008
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Ingår i: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 8, s. 83-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, but also a common colonizer of the upper respiratory tract. The emergence and spread of antibiotic resistant pneumococcal strains has threatened effective therapy. The long-term effects of measures aiming to limit pneumococcal spread are poorly understood. Computational modeling makes it possible to conduct virtual experiments that are impractical to perform in real life and thereby allows a more full understanding of pneumococcal epidemiology and control efforts. Methods: We have developed a contact network model to evaluate the efficacy of interventions aiming to control pneumococcal transmission. Demographic data from Sweden during the mid-2000s were employed. Analyses of the model's parameters were conducted to elucidate key determinants of pneumococcal spread. Also, scenario simulations were performed to assess candidate control measures. Results: The model made good predictions of previous findings where a correlation has been found between age and pneumococcal carriage. Of the parameters tested, group size in day-care centers was shown to be one of the most important factors for pneumococcal transmission. Consistent results were generated from the scenario simulations. Conclusion: We recommend, based on the model predictions, that strategies to control pneumococcal disease and organism transmission should include reducing the group size in day-care centers.
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| 9. |
- Karlsson, Diana, et al.
(författare)
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Modeling the regulation of the competence-evoking quorum sensing network in Streptococcus pneumoniae
- 2007
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Ingår i: Biosystems (Amsterdam. Print). - : Elsevier. - 0303-2647 .- 1872-8324. ; 90:1, s. 211-223
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Tidskriftsartikel (refereegranskat)abstract
- Competence for genetic transformation seems to play a fundamental role in the biology of Streptococcus pneumoniae and is believed to account for serotype switching, evolution of virulence factors, and rapid emergence of antibiotic resistance. The initiation of competence is regulated by the quorum sensing system referred as the ComABCDE pathway. Experimental studies reveal that competence is down-regulated a short time after its induction and several hypotheses about the mechanism(s) responsible for this shut-down have been presented. Possibly, a ComX-dependent gene product, such as a repressor or a phosphatase, is involved. To better understand the down-regulation of the competence-evoking system in S. pneumoniae, a mathematical model was set up. By analyzing the model, we suggest that shut-down of competence possibly occurs at the transcriptional level on the comCDE operon. As a result of introducing a putative comX-dependent repressor, which inhibits expression of comCDE and comX, in the mathematical model, competence is demonstrated to appear in waves. This is supported by experimental studies showing the appearance of successive competence cycles in pneumococcal batch cultures.
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| 10. |
- Lamagni, Theresa L, et al.
(författare)
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Epidemiology of severe Streptococcus pyogenes disease in Europe.
- 2008
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Ingår i: Journal of Clinical Microbiology. - 1098-660X. ; 46:7, s. 2359-2367
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Tidskriftsartikel (refereegranskat)abstract
- The past two decades have brought worrying increases in severe Streptococcus pyogenes diseases globally. To investigate and compare the epidemiological patterns of these diseases within Europe, data on severe S. pyogenes infections were collected through an EU FP-5 funded programme (Strep-EURO). Prospective population-based surveillance of severe S. pyogenes infection diagnosed during 2003 and 2004 was undertaken in eleven countries across Europe (Cyprus, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Romania, Sweden, UK) using a standardised case definition. A total of 5522 cases of severe S. pyogenes infection were identified across the eleven countries during this period. Rates of reported infection varied, reaching 3/100,000 population in the northern European countries. Seasonal patterns of infections showed remarkable congruence between countries. Risk of infection was highest among the elderly, with rates being higher in males than females in most countries. Skin lesions/wounds were the most common predisposing factor, reported in 25% of cases; 21% had no predisposing factors reported. Skin and soft tissue was the most common focus of infection, 32% of patients having cellulitis and 8% necrotizing fasciitis. The overall 7-day case fatality rate was 19%, 44% among cases who developed streptococcal toxic shock syndrome. Findings from Strep-EURO confirm a high incidence of severe S. pyogenes disease in Europe. Furthermore, these results have identified targets for public health intervention, as well as raising awareness of severe S. pyogenes disease across Europe.
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