| 1. |
- Alitalo, Antti, et al.
(författare)
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Expression of complement factor H binding immunoevasion proteins in Borrelia garinii isolated from patients with neuroborreliosis.
- 2005
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Ingår i: Eur J Immunol. - 0014-2980. ; 35:10, s. 3043-3053
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Tidskriftsartikel (refereegranskat)abstract
- The Lyme disease-pathogen Borrelia burgdorferi binds the complement inhibitor factor H (FH) to its outer surface protein E- (OspE) and BbA68-families of lipoproteins. In earlier studies, only serum-resistant strains of the genospecies B. burgdorferi sensu stricto or B. afzelii, but not serum-sensitive B. garinii strains, have been shown to bind FH. Since B. garinii often causes neuroborreliosis in man, we have readdressed the interactions of B. garinii with FH. B. garinii 50/97 strain did not express FH-binding proteins. By transforming the B. garinii 50/97 strain with an OspE-encoding gene from complement-resistant B. burgdorferi (ospE-297), its resistance to serum killing could be increased. OspE genes were detected and cloned from the B. garinii BITS, Pistoia and 40/97 strains by PCR and sequencing. The deduced amino acid sequences differed in an N-terminal lysine-rich FH-binding region from OspE sequences of resistant strains. Recombinant B. garinii BITS OspE protein was found to have a considerably lower FH-binding activity than the B. burgdorferi sensu stricto 297 OspE protein P21 (P21-297). Unlike bacteria that had been kept in culture for a long time, neurovirulent B. garinii strains from neuroborreliosis patients were found to express approximately 27-kDa FH-binding proteins. These were not recognized by polyclonal anti-OspE or anti-BbA68 antibodies. We conclude that B. garinii strains carry ospE genes but have a decreased expression of OspE proteins and a reduced ability to bind FH, especially when grown for prolonged periods in vitro. Recently isolated neuroinvasive B. garinii strains, however, can express FH-binding proteins, which may contribute to the virulence of neuroborreliosis-causing B. garinii strains.
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| 2. |
- Andersson, Marie, 1962-
(författare)
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Immunopathogenesis of relapsing fever borreliosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Relapsing fever (RF) is caused by different species of Borrelia transmitted by soft ticks or by the human body louse. Illness is characterized by reappearing peaks of high concentrations of spirochetes in blood, concordant with fever peaks separated by asymptomatic periods. Neuroborreliosis is one of the most severe manifestations of RF borreliosis. To understand the immune response during early RF, we analyzed immune cells in brain and kidney of mice infected with B. crocidurae during the acute infection. Our results indicate that brain defense is comprised primarily of innate immune cells. Despite the infiltration of innate immune cells, Borrelia was not completely eradicated. A failure of the host brain to clear the bacteria may give the pathogen a niche where it can persist. Using our mouse model, we revealed that Borrelia duttonii could persist in the mouse brain for up to 270 days, without being present in the circulation. The infection was silent with no change in host gene expression, and the spirochetes could re-enter the circulation after immunosuppression. We propose that the brain is used by the pathogen to evade host immunity and serves as a possible natural reservoir for B. duttonii, a spirochete that has rarely been found in any mammalian host other than man. Borrelia-induced complications during pregnancy have been reported, and are especially common in RF. In our established mouse model of gestational RF, we could show that the fetuses suffered from severe pathology and growth retardation, probably as a consequence of placental destruction. We could also show trans-placental transmission of the bacteria leading to neonatal RF. Surprisingly, pregnant dams had a lower bacterial load and less severe disease, showing that pregnancy has a protective effect during RF. We have used the gestational RF model to investigate host factors favoring disease resolution. Because the spleen is the primary organ responsible for trapping and removing blood-borne pathogens, we have compared temporal changes in spleen immune cell populations and cytokine/chemokine induction during the infection. Spleens of pregnant mice had earlier neutrophil infiltration, as well as faster and higher production of pro-inflammatory mediators. This rapid, robust response suggests a more effective host defense. Thus, an enhanced pro-inflammatory response during pregnancy imparts a distinct advantage in controlling the severity of relapsing fever infection.
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| 3. |
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| 5. |
- Bailey, Leslie, 1975-
(författare)
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Infection biology of Chlamydia pneumoniae
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are two main human pathogens in the family of Chlamydiaceae. Different serovars of Chlamydia trachomatis cause sexually-transmitted disease and eye infections whereas C. pneumoniae (TWAR) is a common cause of community-acquired respiratory infection. Chlamydia species are obligate, intracellular bacteria sharing a unique developmental cycle that occurs within a protected vacuole termed an inclusion. These microorganisms can be distinguished by two different forms: the infectious, metabolically inert elementary body (EB) and the reproducing non-infectious form, termed the reticulate body (RB). The cycle is terminated when re-differentiation of RBs back to infectious EBs occurs. Chlamydia possesses a type III secretion system (T3SS) essential for delivery of effector proteins into the host for host-cell interactions. This virulence system has been systematically characterized in several mammalian pathogens. Due to lack of a tractable genetic system for Chlamydia species, we have employed chemical genetics as a strategy to investigate molecular aspects of the T3SS. We have identified that the T3S-inhibitors INP0010 and INP0400 block the developmental cycle and interfere with secretion of T3S effector proteins in C. pneumoniae and C. trachomatis, without any cytotoxic effect. We have further shown that INP0010 decreases initiation of transcription in C. pneumoniae during the early mid-developmental cycle as demonstrated by a novel calculation, useful for measurement of transcription initiation in any intracellular pathogen. The mechanism regulating the signal(s) for primary as well as terminal differentiation of RBs has not been defined in Chlamydia. We show using T3S-inhibitors that INP0010 targets the T3SS and thereby arrests RB proliferation as well as RB to EB re-differentiation of C. pneumoniae as where INP0400 targets the T3SS and provokes a bacterial dissociation from the inclusion membrane presumed to mimic the natural occurrence of terminal differentiation. The effect of INP0010 on iron-responsive genes indicates a role for T3S in iron acquisition. Accordingly, our results suggest the possibility that C. pneumoniae acquires iron via the intracellular trafficking pathway of endocytosed transferrin. Moreover, we have for the first time presented data showing generalized bone loss from C. pneumoniae infection in mice. The infection was associated with increased levels of the bone resorptive cytokines IL-6 and IL-1beta. In addition, an increased sub-population of T-cells expressed RANKL during infection. Additionally, C. pneumoniae established an infection in a human osteoblast cell line in vitro with a similar cytokine profile as seen in vivo, supporting a causal linkage. Collectively, these data may indicate a previously unknown pathological role of C. pneumoniae in generalized bone loss.
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| 6. |
- 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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| 7. |
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| 8. |
- Bergström, Gunnar, et al.
(författare)
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Acceptanskriterier för repor och intryck i plaströr Accpetance criteria for scratches and indentations in plastic pipes
- 2009
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Rapport (refereegranskat)abstract
- Development of materials and laying techniques have arisen the question how scratches and indentations in plastics pipes affect the strength and technical lifetime of pipelines. Scratches may occur both in the manufacturing of the pipes, in connection with the installation and subsequent maintenance. The problems in assessing the failure risk from scratches and indentations are similar for pipes used in gas and water distribution and in district heating applications. Therefore, a broad effort to identify the risks in relation to current pipe materials is technically and economically justified. The project has aimed to evaluate the effect of scratches and indentations on the technical lifetime of plastics pipes and to present criteria for maximum allowable depth of scratches and indentations. The study on pressure pipes focused on the conditions for scratched polyethylene pipes to achieve a lifetime of 50 years. It is noted that a scratch damage can not be judged solely on the basis of its depth and sharpness. To assess the impact of the scratch on the serviceability of the pipe, consideration must also be taken to the material from which the pipe was made and the safety factor used in the design. Extensive pressure tests show that pipes made of modern materials can withstand surface scratches to a higher degree than pipes of older materials. For pipes made of modern bimodal PE80 and PE100 materials, scratches up to 10% depth may be accepted without reduction of rated pressure. However, for pipes of older material, a reduction in pressure may be required already at smaller scratches. The study also indicates that for the same relative scratch depth, a greater reduction in pressure is required with increasing pipe dimension. The study on the non pressure pipes shows that the studied polypropylene pipes resist both deep scratches combined with ovalization and large indentations without any cracks penetrating the pipe wall. However, the extent and development of crazing and surface cracking vary with scratch depth, deformation level and material. The test pipes were subjected to extreme conditions very rarely or never occurring in practice. This suggests that small scratches at moderate ovalization and realistic indentations in temperatures around room temperature do not affect the lifetime of the pipes. One objective of the project was to develop a method for the evaluation of the scratch resistance of a pipe. In the proposed test method the force needed to produce a specified scratch is measured. This force is used as a relative measure of the scratch resistance of a pipe material when compared to other materials. In order to assess to what extent a scratch affects the lifetime of the pipe, the depth of the scratch must be estimated with reasonable accuracy. Since the scratch in many cases is found on existing pipelines the method must be suited for field use. To achieve that a simple instrument for scratch depth measurements was made and evaluated.
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| 9. |
- Bergström, Gunnar, et al.
(författare)
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Accpetance criteria for scratches and indentations in plastic pipes
- 2009
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Rapport (refereegranskat)abstract
- Development of materials and laying techniques have arisen the question how scratches and indentations in plastics pipes affect the strength and technical lifetime of pipelines. Scratches may occur both in the manufacturing of the pipes, in connection with the installation and subsequent maintenance. The problems in assessing the failure risk from scratches and indentations are similar for pipes used in gas and water distribution and in district heating applications. Therefore, a broad effort to identify the risks in relation to current pipe materials is technically and economically justified. The project has aimed to evaluate the effect of scratches and indentations on the technical lifetime of plastics pipes and to present criteria for maximum allowable depth of scratches and indentations. The study on pressure pipes focused on the conditions for scratched polyethylene pipes to achieve a lifetime of 50 years. It is noted that a scratch damage can not be judged solely on the basis of its depth and sharpness. To assess the impact of the scratch on the serviceability of the pipe, consideration must also be taken to the material from which the pipe was made and the safety factor used in the design. Extensive pressure tests show that pipes made of modern materials can withstand surface scratches to a higher degree than pipes of older materials. For pipes made of modern bimodal PE80 and PE100 materials, scratches up to 10% depth may be accepted without reduction of rated pressure. However, for pipes of older material, a reduction in pressure may be required already at smaller scratches. The study also indicates that for the same relative scratch depth, a greater reduction in pressure is required with increasing pipe dimension. The study on the non pressure pipes shows that the studied polypropylene pipes resist both deep scratches combined with ovalization and large indentations without any cracks penetrating the pipe wall. However, the extent and development of crazing and surface cracking vary with scratch depth, deformation level and material. The test pipes were subjected to extreme conditions very rarely or never occurring in practice. This suggests that small scratches at moderate ovalization and realistic indentations in temperatures around room temperature do not affect the lifetime of the pipes. One objective of the project was to develop a method for the evaluation of the scratch resistance of a pipe. In the proposed test method the force needed to produce a specified scratch is measured. This force is used as a relative measure of the scratch resistance of a pipe material when compared to other materials. In order to assess to what extent a scratch affects the lifetime of the pipe, the depth of the scratch must be estimated with reasonable accuracy. Since the scratch in many cases is found on existing pipelines the method must be suited for field use. To achieve that a simple instrument for scratch depth measurements was made and evaluated.
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