| 1. |
- Larsson, Christer, 1975-, et al.
(författare)
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A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice
- 2009
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Ingår i: PLoS Neglected Tropical Diseases. - : PLoS, Public Library of Science. - 1935-2727 .- 1935-2735. ; 3:9, s. e522-
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Tidskriftsartikel (refereegranskat)abstract
- Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.
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| 2. |
- Larsson, Christer, 1975-, et al.
(författare)
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Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
- 2008
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Ingår i: Microbial Pathogenesis. - : Elsevier. - 0882-4010 .- 1096-1208. ; 44:3, s. 262-264
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Tidskriftsartikel (refereegranskat)abstract
- Like several other spirochetes, relapsing fever Borrelia can cause persistent infection of the central nervous system (CNS). By treating mice harboring residual Borrelia duttonii brain infection with the bacteriocidal, cell wall inhibiting antibiotic ceftriaxone, bacteria were cleared from the brain. This shows that the residual infection is not latent but actively growing.
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| 3. |
- Lundqvist, Jenny, 1975-, et al.
(författare)
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Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis
- 2010
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 78:5, s. 1924-1930
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Tidskriftsartikel (refereegranskat)abstract
- About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia can be misdiagnosed with malaria due to similar manifestations and geographic distribution of the two diseases. More alarmingly, high prevalence of concomitant infections with malaria and RF Borrelia has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response towards the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, co-infected animals had higher fatality rate and shorter time to death than both malaria and RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF Borrelia infection. Our study highlights the importance of investigating concomitant infections in vivo to elucidate the immune responses that are involved in the clinical outcome.
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| 4. |
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| 5. |
- Bozzola, Tiago, et al.
(författare)
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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
- 2022
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Ingår i: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7, s. 1890-1900
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
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| 6. |
- Ferndahl, Cecilia, 1975, et al.
(författare)
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Increasing cell biomass in Saccharomyces cerevisiae increases recombinant protein yield: the use of a respiratory strain as a microbial cell factory
- 2010
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Ingår i: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recombinant protein production is universally employed as a solution to obtain the milligram to gram quantities of a given protein required for applications as diverse as structural genomics and biopharmaceutical manufacture. Yeast is a well-established recombinant host cell for these purposes. In this study we wanted to investigate whether our respiratory Saccharomyces cerevisiae strain, TM6*, could be used to enhance the productivity of recombinant proteins over that obtained from corresponding wild type, respiro-fermentative strains when cultured under the same laboratory conditions. Results: Here we demonstrate at least a doubling in productivity over wild-type strains for three recombinant membrane proteins and one recombinant soluble protein produced in TM6* cells. In all cases, this was attributed to the improved biomass properties of the strain. The yield profile across the growth curve was also more stable than in a wild-type strain, and was not further improved by lowering culture temperatures. This has the added benefit that improved yields can be attained rapidly at the yeast's optimal growth conditions. Importantly, improved productivity could not be reproduced in wild-type strains by culturing them under glucose fed-batch conditions: despite having achieved very similar biomass yields to those achieved by TM6* cultures, the total volumetric yields were not concomitantly increased. Furthermore, the productivity of TM6* was unaffected by growing cultures in the presence of ethanol. These findings support the unique properties of TM6* as a microbial cell factory. Conclusions: The accumulation of biomass in yeast cell factories is not necessarily correlated with a proportional increase in the functional yield of the recombinant protein being produced. The respiratory S. cerevisiae strain reported here is therefore a useful addition to the matrix of production hosts currently available as its improved biomass properties do lead to increased volumetric yields without the need to resort to complex control or cultivation schemes. This is anticipated to be of particular value in the production of challenging targets such as membrane proteins.
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| 7. |
- Flentie, Kelly, et al.
(författare)
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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Scionces of the United States of America. - 0027-8424 .- 1091-6490. ; 116:21, s. 10510-10517
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
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| 8. |
- Henricsson, Cecilia, 1975, et al.
(författare)
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Engineering of a novel Saccharomyces cerevisiae wine strain with a respiratory phenotype at high external glucose concentrations
- 2005
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Ingår i: Applied and Environmental Microbiology. - 0099-2240 .- 1098-5336. ; 71:10, s. 6185-6192
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Tidskriftsartikel (refereegranskat)abstract
- The recently described respiratory strain Saccharomyces cerevisiae KOY.TM6*P is, to our knowledge, the only reported strain of S. cerevisiae which completely redirects the flux of glucose from ethanol fermentation to respiration, even at high external glucose concentrations (27). In the KOY.TM6*P strain, portions of the genes encoding the predominant hexose transporter proteins, Hxt1 and Hxt7, were fused within the regions encoding transmembrane (TM) domain 6. The resulting chimeric gene, TM6*, encoded a chimera composed of the amino-terminal half of Hxt1 and the carboxy-terminal half of Hxt7. It was subsequently integrated into the genome of an hxt null strain. In this study, we have demonstrated the transferability of this respiratory phenotype to the V5 hxt1-7 strain, a derivative of a strain used in enology. We also show by using this mutant that it is not necessary to transform a complete hxt null strain with the TM6* construct to obtain a nonethanol- producing phenotype. The resulting V5.TM6*P strain, obtained by transformation of the V5 hxt1-7 strain with the TM6* chimeric gene, produced only minor amounts of ethanol when cultured on external glucose concentrations as high as 5%. Despite the fact that glucose flux was reduced to 30% in the V5.TM6*P strain compared with that of its parental strain, the V5.TM6*P strain produced biomass at a specific rate as high as 85% that of the V5 wild-type strain. Even more relevant for the potential use of such a strain for the production of heterologous proteins and also of low-alcohol beverages is the observation that the biomass yield increased 50% with the mutant compared to its parental strain.
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| 9. |
- Larsson, Christer, 1975-, et al.
(författare)
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A novel and simple method for laboratory diagnosis of relapsing Fever borreliosis.
- 2008
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Ingår i: The Open Microbiology Journal. - : Bentham Science Publishers Ltd.. - 1874-2858. ; 2, s. 10-2
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Tidskriftsartikel (refereegranskat)abstract
- Relapsing fever caused by Borrelia bacteria is often obscured by malaria and incorrectly treated. Here a novel method for diagnosis is presented. The method is cheap, simple and requires minimal laboratory material. Despite its simplicity, the method shows surprisingly high sensitivity, detecting concentrations less than 10 bacteria/ml blood.
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| 10. |
- Larsson, Christer, 1975-, et al.
(författare)
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Complications of pregnancy and transplacental transmission of relapsing-fever borreliosis
- 2006
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 194:10, s. 1367-1374
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Tidskriftsartikel (refereegranskat)abstract
- Relapsing-fever borreliosis caused by Borrelia duttonii is a common cause of complications of pregnancy, miscarriage, and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever infection for the study of the pathological development of these complications. We demonstrate that B. duttonii infection during pregnancy results in intrauterine growth retardation, as well as placental damage and inflammation, impaired fetal circulation, and decreased maternal hemoglobin levels. We show that spirochetes frequently cross the maternal-fetal barrier, resulting in congenital infection. Furthermore, we compared the severity of infection in pregnant and nonpregnant mice and show that pregnancy has a protective effect. This model closely parallels the consequences of human gestational infection, and our results provide insight into the mechanisms behind the complications of pregnancy that have been reported in human relapsing-fever infection.
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| 11. |
- Larsson, Christer, 1975-, et al.
(författare)
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Current issues in relapsing fever
- 2009
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Ingår i: Current Opinion in Infectious Diseases. - : Lippincott Williams & Wilkins. - 0951-7375 .- 1473-6527. ; 22:5, s. 443-449
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE OF REVIEW: Relapsing fever has the highest incidence of any bacterial disease in Africa and a massive epidemic potential due to current political turmoil in the Horn of Africa. This review focuses on recent advances in diagnostics, molecular biology and host-pathogen interactions. RECENT FINDINGS: Complete relapsing fever genomes have recently been published, and the first site-specific genetic knockout complementation has been performed. Relapsing fever has gone from being a neglected disease to garnering interest in aspects such as tissue invasion, membrane biochemistry and complement evasion. Relapsing fever symptoms are variable, and the disease is commonly misdiagnosed as, for example, malaria. Although relapsing fever is considered a transient disease, it persists as a residual infection in the brain, which can be reactivated on immunosuppression. Therefore, single-dose antibiotic treatment should be avoided. Instead, treatment should cover a longer period, similar to the recommended regime for Lyme disease. Relapsing fever is a common cause of pregnancy complications such as intrauterine growth retardation and placental damage with spirochaetes crossing the maternal-foetal barrier, resulting in congenital infection. SUMMARY: Although relapsing fever remains a big problem, recently described host-pathogen interactions, diagnostics and molecular biology advances such as completed genome sequences and the dawn of genetic tools have brought relapsing fever research into the 21st century.
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| 12. |
- Larsson, Christer, 1975-, et al.
(författare)
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First Record of Lyme Disease Borrelia in the Arctic
- 2007
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Ingår i: Vector Borne and Zoonotic Diseases. - : Mary Ann Liebert Inc. - 1530-3667 .- 1557-7759. ; 7:3, s. 453-456
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Tidskriftsartikel (refereegranskat)abstract
- The epidemiology and ecology of Lyme disease is very complex, and its reported geographical distribution is constantly increasing. Furthermore, the involvement of birds in long distance dispersal and their role as reservoir hosts is now well established. In this study, we have shown that sea birds in the Arctic region of Norway carry Ixodes uriae ticks infected with Lyme disease Borrelia garinii spirochetes. Interestingly, DNA sequencing showed that these isolates are closely related to B. garinii previously isolated from birds, as well as from clinical specimens in northern Europe.
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| 13. |
- Larsson, Christer, 1975-
(författare)
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Pathobiology of African relapsing fever Borrelia
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Relapsing fever (RF) is a disease caused by tick- or louse-transmitted bacteria of the genus Borrelia. It occurs worldwide but is most common in Africa where it is one of the most prevalent bacterial diseases. The main manifestation is a recurring fever which coincides with massive numbers of bacteria in the blood. Severity ranges from asymptomatic to fatal.RF is usually considered a transient disease. In contrast, B. duttonii causes a persistent, residual brain infection in C57BL/6 mice which remains long time after the bacteria are cleared from the blood. The host gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor do they cause noticeable tissue damage. This is probably due to the quite low number of bacteria residing in the brain. The silent infection can be reactivated by immunosuppression allowing bacteria to re-enter the blood. To investigate if the residual infection is in a quiescent state or if the bacteria are actively dividing, mice with residual brain infection were treated with the cell-wall disrupting antibiotic ceftriaxone, which is only active against dividing bacteria. Since all mice were cured by ceftriaxone we conclude that the bacteria are actively growing in the brain rather than being in a latent, dormant state. The brain is used as an immunoprivileged site to escape host immune defence and probably as a reservoir for bacteria.RF is a common cause of pregnancy complications, miscarriage and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever to study the pathological development of these complications. B. duttonii infection during pregnancy results in intrauterine growth retardation as well as placental damage and inflammation. Spirochetes cross the maternal-foetal barrier, resulting in congenital infection. Further, pregnancy has a protective effect, resulting in milder disease during pregnancy.A clinic-based study to investigate the presence of RF in Togo was performed. Blood from patients with fever were examined for RF by microscopy, GlpQ ELISA and PCR. About 10% of the patients were positive by PCR and 13% had antibodies to GlpQ. Many RF patients originally had a misdiagnosis of malaria, which resulted in ineffective treatment. The inability of microscopic analysis to detect spirochetes demonstrates the need for tests with greater sensitivity. To provide simple, fast, cheap and sensitive diagnostics using equipment available in small health centres, a method based on enrichment of bacteria by centrifugation and detection by Giemsa staining was developed which detects <10 spirochetes/ml.To study the phylogeny of RF, IGS and glpQ were sequenced and neighbor joining trees were constructed. B. persica and B. hispanica were distant from the other species iswhereas B. crocidurae appeared to be a heterogeneous species. B. duttonii is polyphyletic in relation to B. recurrentis suggesting that the two species may in fact be the same or have a polyphyletic origin.
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| 14. |
- Larsson, Christer, 1975-, et al.
(författare)
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Persistent brain infection and disease reactivation in relapsing fever borreliosis
- 2006
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Ingår i: Microbes and infection. - : Elsevier. - 1286-4579 .- 1769-714X. ; 8:8, s. 2213-2219
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Tidskriftsartikel (refereegranskat)abstract
- Relapsing fever, an infection caused by Borrelia spirochetes, is generally considered a transient, self-limiting disease in humans. The present study reveals that murine infection by Borrelia duttonii can be reactivated after an extended time as a silent infection in the brain, with no bacteria appearing in the blood and spirochete load comparable to the numbers in an infected tick. The host cerebral gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor cause noticeable tissue damage. Silent infection can be reactivated by immunosuppression, inducing spirochetemia comparable to that of initial densities. B. duttonii has never been found in any host except man and the tick vector. We therefore propose the brain to be a possible natural reservoir of the spirochete. The view of relapsing fever as an acute disease should be extended to include in some cases prolonged persistence, a feature characteristic of the related spirochetal infections Lyme disease and syphilis.
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| 15. |
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| 16. |
- Lundqvist, Jenny, 1975-, et al.
(författare)
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Mixed infection decreases malaria burden and escalate relapsing fever
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia are misdiagnosed with malaria due to similar manifestation and geographic distribution of the two diseases. More alarmingly, high prevalence of mixed infections with malaria and RF Borrelia has been reported. Therefore, we developed a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas parasitemia decreased 15-fold. This may be explained by polarization of the host immune response towards the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts succumb to sepsis. Furthermore, secondary malaria infection can reactivate a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of dormant RF Borrelia infection. Mixed infection also resulted in severe anemia even though the parasite counts were low. Our study highlights the importance of investigating mixed infections in vivo to elucidate the immune responses that are involved in the clinical outcome, and it also emphasizes the urgent need for improved diagnostics of malaria and other infectious diseases such as RF Borrelia.
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| 17. |
- Otterstedt, Karin, et al.
(författare)
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Switching the mode of metabolism in the yeast Saccharomyces cerevisiae.
- 2004
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Ingår i: Embro reports. - : EMBO. - 1469-221X .- 1469-3178. ; 5:5, s. 532-537
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Tidskriftsartikel (refereegranskat)abstract
- The biochemistry of most metabolic pathways is conserved from bacteria to humans, although the control mechanisms are adapted to the needs of each cell type. Oxygen depletion commonly controls the switch from respiration to fermentation. However, Saccharomyces cerevisiae also controls that switch in response to the external glucose level. We have generated an S. cerevisiae strain in which glucose uptake is dependent on a chimeric hexose transporter mediating reduced sugar uptake. This strain shows a fully respiratory metabolism also at high glucose levels as seen for aerobic organisms, and switches to fermentation only when oxygen is lacking. These observations illustrate that manipulating a single step can alter the mode of metabolism. The novel yeast strain is an excellent tool to study the mechanisms underlying glucose-induced signal transduction.
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| 18. |
- Spiegelberg, Christer, 1975-
(författare)
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Friction and wear in rolling and sliding contacts
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mechanical products are always expected to perform better, last longer, be more environmentally friendly and preferably cost less. Rolling and sliding contacts are found in many mechanical products, and friction and wear in the contacts have a direct impact on the products’ ability to meet these demands. Friction directly influences efficiency; low friction is often wanted to minimize power loss and fuel consumption. Wear generally shortens the lifetime, leading to more frequent service stops and increased costs. Increased demands on the products also means increased demands on the contacts in the products; contacts must work with higher loads and less friction, and they must last longer. The combination of increased demands and the high levels of sophistication of many products puts the spotlight on the contacts, and it becomes perhaps more important than ever to be able to predict and optimize their tribological performance. Simulation of systems with rolling and sliding contacts is a useful tool to understand the contact conditions and to help optimize their performance. This thesis is focused on friction and wear of boundary-lubricated, non-conformal rolling and sliding contacts. It presents a 3D brush model for transient friction in rolling and sliding contacts that can handle rough surfaces, varying surface velocities and varying normal load. Friction is simulated in interference mesh gears, cam mechanisms, a system with a roller between two planes and a system with a contact between two discs. Friction is also studied experimentally in interference mesh gears and in the contact between two discs. A wear model based on a generalized form of Archard’s wear law and the single-point observation method is used to simulate wear in the contact between the rocker arm pad and valve bridge in a cam mechanism of a diesel engine. The results show that the friction model can be used to simulate friction in both motion- controlled and force-controlled systems. The model can be used for both detailed contact studies and studies of the overall behaviour of systems with rolling and sliding contacts. Simulations and experiments show that the efficiency in interference mesh gears decreases significantly depending on the combination of mesh force pressing the gears together and the load on the output shaft. It is also seen that the torque loss varies heavily during a gear mesh depending on the position of the gear teeth and the number of contact points. The results from the simulations are consistent with the experimental results. The simulations of the cam-roller contact show that the creep in the contact is low except at high cam speeds when there is a period with high creep when the contact is close to the tip of the camshaft. The simulations of the rocker arm pad and valve bridge show that the contact radii of the wear pad and the position of the centre of the wear pad radii have a strong influence on the amount of wear. The simulations also show that the change of surface shapes due to wear can worsen contact conditions with high normal pressures. The simulations and experiments of force-controlled systems show that contacts can have a strong influence on a system’s behaviour. The contact acts as a spring damper system and can cause oscillations of the system. Simulations show that the oscillations could, at least in part, be explained by the surface roughness. Simulations also show that the creep in the contact is influenced by the contact stiffness and that the contact stiffness is lower for rough surfaces than for smooth. The experiments also show that the creep is higher for a lubricated contact than a dry contact.
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| 19. |
- Thein, Marcus, et al.
(författare)
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Oms38 is the first identified pore-forming protein in the outer membrane of relapsing fever spirochetes
- 2008
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Ingår i: Journal of Bacteriology. - 0021-9193 .- 1098-5530. ; 190:21, s. 7035-7042
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Tidskriftsartikel (refereegranskat)abstract
- Relapsing fever is a worldwide, endemic disease caused by several spirochetal species belonging to the genus Borrelia. During the recurring fever peaks, borreliae proliferate remarkably quickly compared to the slow dissemination of Lyme disease Borrelia and therefore require efficient nutrient uptake from the blood of their hosts. This study describes the identification and characterization of the first relapsing fever porin, which is present in the outer membranes of B. duttonii, B. hermsii, B. recurrentis, and B. turicatae. The pore-forming protein was purified by hydroxyapatite chromatography and designated Oms38, for outer membrane-spanning protein of 38 kDa. Biophysical characterization of Oms38 was done by using the black lipid bilayer method, demonstrating that Oms38 forms small, water-filled channels of 80 pS in 1 M KCl that did not exhibit voltage-dependent closure. The Oms38 channel is slightly selective for anions and shows a ratio of permeability for cations over anions of 0.41 in KCl. Analysis of the deduced amino acid sequences demonstrated that Oms38 contains an N-terminal signal sequence which is processed under in vivo conditions. Oms38 is highly conserved within the four studied relapsing fever species, sharing an overall amino acid identity of 58% and with a strong indication for the presence of amphipathic beta-sheets.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Tükenmez, Hasan, 1987-, et al.
(författare)
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Corticosteroids protect infected cells against mycobacterial killing in vitro
- 2019
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 511:1, s. 117-121
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Tidskriftsartikel (refereegranskat)abstract
- The effect of corticosteroids on human physiology is complex and their use in tuberculosis patients remains controversial. In a high-throughput screening approach designed to discover virulence inhibitors, several corticosteroids were found to prevent cytolysis of fibroblasts infected with mycobacteria. Further experiments with Mycobacterium tuberculosis showed anti-cytolytic activity in the 10 nM range, but no effect on bacterial growth or survival in the absence of host cells at 20 mu M. The results from a panel of corticosteroids with various affinities to the glucocorticoid- and mineralocorticoid receptors indicate that the inhibition of cytolysis most likely is mediated through the glucocorticoid receptor. Using live-imaging of M. tuberculosis-infected human monocyte-derived macrophages, we also show that corticosteroids to some extent control intracellular bacteria. In vitro systems with reduced complexity are to further study and understand the interactions between bacterial infection, immune defense and cell signaling. (C) 2019 The Authors. Published by Elsevier Inc.
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| 25. |
- Tükenmez, Hasan, 1987-, et al.
(författare)
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Mycobacterium tuberculosis Rv3160c is a TetR-like transcriptional repressor that regulates expression of the putative oxygenase Rv3161c
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a major health threat listed among the top 10 causes of death worldwide. Treatment of multidrug-resistant Mtb requires use of additional second-line drugs that prolong the treatment process and result in higher death rates. Our team previously identified a 2-pyridone molecule (C10) that blocks tolerance to the first-line drug isoniazid at C10 concentrations that do not inhibit bacterial growth. Here, we discovered that the genes rv3160c and rv3161c are highly induced by C10, which led us to investigate them as potential targets. We show that Rv3160c acts as a TetR-like transcriptional repressor binding to a palindromic sequence located in the rv3161c promoter. We also demonstrate that C10 interacts with Rv3160c, inhibiting its binding to DNA. We deleted the rv3161c gene, coding for a putative oxygenase, to investigate its role in drug and stress sensitivity as well as C10 activity. This Δrv3161c strain was more tolerant to isoniazid and lysozyme than wild type Mtb. However, this tolerance could still be blocked by C10, suggesting that C10 functions independently of Rv3161c to influence isoniazid and lysozyme sensitivity.
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| 26. |
- Wallgard, Elisabet, et al.
(författare)
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Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature.
- 2008
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636 .- 1079-5642. ; 28:8, s. 1469-76
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Pathological angiogenesis is an integral component of many diseases. Antiangiogenesis and vascular targeting are therefore promising new therapeutic principles. However, few endothelial-specific putative drug targets have been identified, and information is still limited about endothelial-specific molecular processes. Here we aimed at determining the endothelial cell-specific core transcriptome in vivo. METHODS AND RESULTS: Analysis of publicly available microarray data identified a mixed vascular/lung cluster of 132 genes that correlated with known endothelial markers. Filtering against kidney glomerular/nonglomerular and brain vascular/nonvascular microarray profiles separated contaminating lung markers, leaving 58 genes with broad and specific microvascular expression. More than half of these have not previously been linked to endothelial functions or studied in detail before. The endothelial cell-specific expression of a selected subset of these, Eltd1, Gpr116, Ramp2, Slc9a3r2, Slc43a3, Rasip1, and NM_023516, was confirmed by real-time quantitative polymerase chain reaction and/or immunohistochemistry. CONCLUSIONS: We have used a combination of publicly available and own microarray data to identify 58 gene transcripts with broad yet specific expression in microvascular endothelium. Most of these have unknown functions, but many of them are predicted to be cell surface expressed or implicated in cell signaling processes and should therefore be explored as putative microvascular drug targets.
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