| 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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