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  • 1.
    Barcena-Uribarri, Ivan
    et al.
    Universität Würzburg, Germany.
    Thein, Marcus
    Universität Würzburg and Jacobs University Bremen, Germany.
    Maier, Elke
    Universität Würzburg, Germany.
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    Universität Würzburg, Germany.
    Use of Nonelectrolytes Reveals the Channel Size and Oligomeric Constitution of the Borrelia burgdorferi P66 Porin2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e78272-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the Lyme disease spirochete Borrelia burgdorferi, the outer membrane protein P66 is capable of pore formation with an atypical high single-channel conductance of 11 nS in 1 M KCl, which suggested that it could have a larger diameter than 'normal' Gram-negative bacterial porins. We studied the diameter of the P66 channel by analyzing its single-channel conductance in black lipid bilayers in the presence of different nonelectrolytes with known hydrodynamic radii. We calculated the filling of the channel with these nonelectrolytes and the results suggested that nonelectrolytes (NEs) with hydrodynamic radii of 0.34 nm or smaller pass through the pore, whereas neutral molecules with greater radii only partially filled the channel or were not able to enter it at all. The diameter of the entrance of the P66 channel was determined to be <= 1.9 nm and the channel has a central constriction of about 0.8 nm. The size of the channel appeared to be symmetrical as judged from one-sidedness of addition of NEs. Furthermore, the P66-induced membrane conductance could be blocked by 80-90% by the addition of the nonelectrolytes PEG 400, PEG 600 and maltohexaose to the aqueous phase in the low millimolar range. The analysis of the power density spectra of ion current through P66 after blockage with these NEs revealed no chemical reaction responsible for channel block. Interestingly, the blockage of the single-channel conductance of P66 by these NEs occurred in about eight subconductance states, indicating that the P66 channel could be an oligomer of about eight individual channels. The organization of P66 as a possible octamer was confirmed by Blue Native PAGE and immunoblot analysis, which both demonstrated that P66 forms a complex with a mass of approximately 460 kDa. Two dimension SDS PAGE revealed that P66 is the only polypeptide in the complex.

  • 2.
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Structure and Function of the Borrelia burgdorferi Porins, P13 and P662015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Borrelia burgdorferi är en bakterie med många unika egenskaper som orsakar sjukdomen Lyme borrelios. Borrelia kan idag lätt behandlas med antibiotika om sjukdomen upptäcks i ett tidigt stadium. Det är först om sjukdomen tillåts fortgå som symptom som nervsmärta och ansiktsförlamning kan uppstå och dessutom vara svåra att koppla till en Borrelia-infektion. Multiresistenta bakterier har blivit en stor del av vår vardag och även om Borrelia-bakterierna idag inte är resistenta mot flertalet antibiotika är det kanske speciellt viktigt, innan det är för sent, med forskning som kan leda till upptäckter av unika angreppsställen för nya läkemedel.

    Målet med denna avhandling var att studera hur två Borrelia proteiner, P13 och P66, ser ut, är uppbyggda och även vilken funktion de har. Dessa proteiner är tänkbara vaccinkandidater eftersom de sitter i yttre membranet hos bakterierna och sticker ut på ytan mot våra värdceller, vilket gör att vi reagerar mot dem vid en infektion. P13 och P66 är också viktiga kanaler för bakterierna vid upptag av näringsämnen och byggstenar från omgivningen. Ämnen som bakterierna inte kan producera själva. Pga. denna funktion är P13 och P66 tänkbara proteiner för blockering med ett läkemedel som skulle förhindra bakterien från att föröka sig i och med att de förlorar möjligheten att tillgodogöra sig näring. Detta i sin tur skulle leda till att vårt eget immunförsvar hinner rensa undan bakterierna innan infektionen blivit för stor och vi blivit sjuka. P66 har förutom porin funktionen även en adhesions funktion när proteinet kan binda integriner som sitter på olika typer av celler i vår kropp, bl. a. immunceller och epitelceller i våra blodkärl och vävnader. Den integrin bindande funktionen är viktig för bakterierna vid en infektion eftersom det gör det möjligt för bakterierna att binda till våra celler. Ett steg som är viktigt för att de senare ska kunna ta sig ut från blodkärlen till våra vävnader.

    P13 och P66 visade sig kunna bilda stora proteinkomplex i ytter membranet hos bakterierna med en storlek på 300 kDa respektive 420 kDa. De är inga specifika poriner som bara kan transportera en viss typ av molekyl med t.ex. en viss laddning, utan kan ombesörja upptaget av många olika typer av ämnen. Eliminering av p66 orsakade att ett annat adhesionsprotein, uppreglerades. En omplacering av ett normalt cytoplasmatiskt lokaliserat chaperon-protein till ytter-membranet hos bakterierna kunde också ses i frånvaro av P66. Chaperonet GroEL har i andra bakterier, bl. a. Helicobacter pylori, bakterien som orsakar magsår, beskrivits som ett protein som kan förflytta sig till ytan av bakterierna och där ha en liknande funktion som P66, dvs. att binda extracellulära matrisprotein. Förändringen i uttryck av adhesionsproteinet och förflyttningen av chaperonet till membranet var en följd av p66-eliminering och mest troligt ett sätt för bakterierna att komplettera den förlorade integrinbindande funktionen av P66.

    Det har tidigare visats att poriner är involverade i skyddet mot osmotisk stress i andra bakterier. Denna funktion hos P13 och P66 i Borrelia kunde inte ses när bakterier utsattes för osmotisk stress med glycerol, som orsakar en form av membranstress. Däremot kunde vi med hjälp av transkriptomanalys se att Borrelia-bakterier uppreglerade transkriptionen av två paraloger till P13 vid hyper-osmotisk stress. Borrelia bakteriens användning av dessa paraloga proteiner har tidigare trotts ske enbart i frånvaro av ett funktionellt P13 protein. Nu visade det sig att P13-paraloger har en egen funktion även i närvaro av P13, nämligen att vara involverade i regleringen av hyperosmotisk stress och därmed skydda bakterierna i denna stressituation. Andra gener som påverkades av osmotisk stress med glycerol var gener för stressfaktorer och pumpar i inre membranet hos bakterien.

  • 3.
    Bonde, Mari
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Olofsson, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Frost, Mikaela
    Jegerschöld, Caroline
    Karolinska Institutet, Sweden.
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sandblad, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Structural analysis of the B. burgdorferi integral outer membrane protein, P13, in lipid bilayer NanodiscsManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 4.
    Bonde, Mari
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Östberg, Yngve
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Bunikis, Ignas
    Uppsala University.
    Nyunt Wai, Sun
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Effects of osmotic stress in P13 and P66 deficient Borrelia burgdorferi mutantsManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 5.
    Bunikis, Ignas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kutschan-Bunikis, Sabrina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Multiplex PCR as a tool for validating plasmid content of Borrelia burgdorferi.2011Ingår i: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 86, nr 2, s. 243-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Borrelia burgdorferi has an unusual genomic structure containing 21 plasmids. These plasmids carry genes that are essential for infectivity and survival of the spirochetes in vivo. Several plasmids are lost during cultivation in vitro, which might lead to a heterogeneous population after multiple passages and loss of infectivity in laboratory animals. Herein, we present a simple and inexpensive multiplex PCR method that detects the complete plasmid profile of B. burgdorferi B31 in just two PCR tubes.

  • 6. Bárcena-Uribarri, Iván
    et al.
    Thein, Marcus
    Barbot, Mariam
    Sans-Serramitjana, Eulalia
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Mentele, Reinhard
    Lottspeich, Friedrich
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    Study of the protein complex, pore diameter, and pore-forming activity of the Borrelia burgdorferi P13 porin2014Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, nr 27, s. 18614-18624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    P13 is one of the major outer membrane proteins of Borrelia burgdorferi. Previous studies described P13 as a porin. In the present study some structure and function aspects of P13 were studied. P13 showed according to lipid bilayer studies a channel-forming activity of 0.6 nanosiemens in 1 M KCl. Single channel and selectivity measurements demonstrated that P13 had no preference for either cations or anions and showed no voltage-gating up to +/-100 mV. Blue native polyacrylamide gel electrophoresis was used to isolate and characterize the P13 protein complex in its native state. The complex had a high molecular mass of about 300 kDa and was only composed of P13 monomers. The channel size was investigated using non-electrolytes revealing an apparent diameter of about 1.4 nm with a 400-Da molecular mass cut-off. Multichannel titrations with different substrates reinforced the idea that P13 forms a general diffusion channel. The identity of P13 within the complex was confirmed by second dimension SDS-PAGE, Western blotting, mass spectrometry, and the use of a p13 deletion mutant strain. The results suggested that P13 is the protein responsible for the 0.6-nanosiemens pore-forming activity in the outer membrane of B. burgdorferi.

  • 7.
    Bárcena-Uribarri, Iván
    et al.
    Universität Würzburg, Germany.
    Thein, Marcus
    Universität Würzburg and Jacobs University Bremen, Germany.
    Maier, Elke
    Universität Würzburg, Germany.
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bunikis, Ignas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    Universität Würzburg, Germany.
    Use of nonelectrolytes reveals the channel size and oligomeric constitution of the Borrelia burgdorferi P66 porinManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The outer membrane protein P66 of the Lyme disease spirochete Borrelia burgdorferi is capable of pore formation with an atypical high single-channel conductance of 11 nS in 1 M KCl. We studied in a non-theoretical manner the diameter of the P66 channel by analyzing its single-channel conductance in black lipid bilayers in the presence of different nonelectrolytes with known hydrodynamic radii. Furthermore, we calculated the filling of the channel with these nonelectrolytes and the results revealed that nonelectrolytes with hydrodynamic radii of 0.34 nm or smaller pass through the pore, whereas neutral molecules with greater radii only partially filled the channel or were not able to enter it at all. Thus, the diameter of the P66 entrance was determined to be ≤ 1.9 nm with a constriction site diameter of about 0.7 nm. Furthermore, the P66-induced membrane conductance could be blocked by 80-90% after addition of the nonelectrolytes PEG 400, PEG 600 and maltohexaose in the low millimolar range. Interestingly, the analysis of the power density spectra of P66 after blockage with nonelectrolytes revealed no chemical interaction responsible for channel block. The blockage of one P66 single-channel conductance unit of 11 nS occurred by seven subconducting states, thus indicating a heptameric organization of the P66 oligomer. This organization of P66 as a heptamer was confirmed by Blue Native PAGE and immunoblot analysis, which demonstrated that P66 forms a complex with a mass of approximately 460 kDa.

  • 8.
    Bárcena-Uribarri, Iván
    et al.
    University of Würzburg.
    Thein, Marcus
    Max Planck Institute for Developmental Biology.
    Sacher, Anna
    German Cancer Research Center.
    Bunikis, Ignas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    University of Würzburg.
    P66 porins are present in both Lyme disease and relapsing fever spirochetes: a comparison of the biophysical properties of P66 porins from six Borrelia species2010Ingår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1798, nr 6, s. 1197-1203Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genus Borrelia is the cause of the two human diseases: Lyme disease (LD) and relapsing fever (RF). BothLD and RF Borrelia species are obligate parasites and are dependent on nutrients provided by their hosts. Thefirst step of nutrient uptake across the outer membrane of these Gram-negative bacteria is accomplished bywater-filled channels, so-called porins. The knowledge of the porin composition in the outer membranes ofthe different pathogenic Borrelia species is limited. Only one porin has been described in relapsing feverspirochetes to date, whereas four porins are known to be present in Lyme disease agents. From these, theBorrelia burgdorferi outer membrane channel P66 is known to act as an adhesin and was well studied as aporin. To investigate if P66 porins are expressed and similarly capable of pore formation in other Borreliacausing Lyme disease or relapsing fever three LD species (B. burgdorferi, B. afzelii, B. garinii) and three RFspecies (B. duttonii, B. recurrentis and B. hermsii) were investigated for outer membrane proteins homologousto P66. A search in current published RF genomes, comprising the ones of B. duttonii, B. recurrentis and B.hermsii, indicated that they all contained P66 homologues. The P66 homologues of the six Borrelia specieswere purified to homogeneity and their pore-forming abilities as well as the biophysical properties of thepores were analyzed using the black lipid bilayer assay.

  • 9.
    Marcus, Thein
    et al.
    University of Würzburg.
    Bonde, Mari
    Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten).
    Bunikis, Ignas
    Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten).
    Denker, Katrin
    University of Würzburg.
    Sickmann, Albert
    University of Würzburg.
    Bergström, Sven
    Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    University of Würzburg.
    DipA, a pore-forming protein in the outer membrane of Lyme disease spirochetes exhibits specificity for the permeation of dicarboxylatesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Lyme disease Borrelia are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borrelia. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a single-channel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl) were obtained among the 11 tested anions for oxaloacetate, 2‑oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species.

  • 10. Orikiiriza, Judy
    et al.
    Surowiec, Izabella
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lindquist, Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Bonde, Mari
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Normark, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar. Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Lipid response patterns in acute phase paediatric Plasmodium falciparum malaria2017Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, nr 4, artikel-id 41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Several studies have observed serum lipid changes during malaria infection in humans. All of them were focused at analysis of lipoproteins, not specific lipid molecules. The aim of our study was to identify novel patterns of lipid species in malaria infected patients using lipidomics profiling, to enhance diagnosis of malaria and to evaluate biochemical pathways activated during parasite infection.

    Methods: Using a multivariate characterization approach, 60 samples were representatively selected, 20 from each category (mild, severe and controls) of the 690 study participants between age of 0.5–6 years. Lipids from patient’s plasma were extracted with chloroform/methanol mixture and subjected to lipid profiling with application of the LCMS-QTOF method.

    Results: We observed a structured plasma lipid response among the malaria-infected patients as compared to healthy controls, demonstrated by higher levels of a majority of plasma lipids with the exception of even-chain length lysophosphatidylcholines and triglycerides with lower mass and higher saturation of the fatty acid chains. An inverse lipid profile relationship was observed when plasma lipids were correlated to parasitaemia.

    Conclusions: This study demonstrates how mapping the full physiological lipid response in plasma from malaria-infected individuals can be used to understand biochemical processes during infection. It also gives insights to how the levels of these molecules relate to acute immune responses.

  • 11. Ristow, Laura
    et al.
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Lin, Yi-Pin
    Sato, Hiromi
    Curtis, Michael
    Wesley, Erin
    Hahn, Beth
    Fang, Juan
    Wilcox, David
    Leong, John
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Coburn, Jenifer
    Integrin binding by Borrelia burgdorferi P66 facilitates dissemination but is not required for infectivity2015Ingår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 17, nr 7, s. 1021-1036Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    P66, a Borrelia burgdorferi surface protein with porin and integrin-binding activities, is essential for murine infection. The role of P66 integrin-binding activity in B. burgdorferi infection was investigated and found to affect transendothelial migration. The role of integrin binding, specifically, was tested by mutation of two amino acids (D205A,D207A) or deletion of seven amino acids (Del202–208). Neither change affected surface localization or channel-forming activity of P66, but both significantly reduced binding to αvβ3. Integrin-binding deficient B. burgdorferi strains caused disseminated infection in mice at 4 weeks post-subcutaneous inoculation, but bacterial burdens were significantly reduced in some tissues. Following intravenous inoculation, the Del202–208 bacteria were below the limit of detection in all tissues assessed at 2 weeks post-inoculation, but bacterial burdens recovered to wild-type levels at 4 weeks post-inoculation. The delay in tissue colonization correlated with reduced migration of the Del202–208 strains across microvascular endothelial cells, similar to Δp66bacteria. These results indicate that integrin binding by P66 is important to efficient dissemination of B. burgdorferi, which is critical to its ability to cause disease manifestations in incidental hosts and to its maintenance in the enzootic cycle.

  • 12.
    Surowiec, Izabella
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gouveia-Figueira, Sandra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children2017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, artikel-id 358Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.

    Methods: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA (R)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).

    Results: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.

    Conclusions: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

  • 13.
    Surowiec, Izabella
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Orikiiriza, Judy
    Karlsson, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Nelson, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kyamanwa, Patrick
    Karenzi, Ben
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar. nfectious Diseases Institute, School of Medicine and Health Sciences, Makerere University, Uganda.
    Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria2015Ingår i: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 2, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Accuracy in malaria diagnosis and staging is vital in order to reduce mortality and post infectious sequelae. Herein we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods: A group of 421 patients between six months and six years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192 and 122 individuals respectively. A multivariate design was used as basis for representative selection of twenty patients in each category. Patient plasma was subjected to Gas Chromatography-Mass Spectrometry analysis and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in-vivo model where metabolic profiles were discernible over time of infection. Results: A two-component principal component analysis (PCA) revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, two sub-groups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusion: Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

  • 14. Thein, Marcus
    et al.
    Bonde, Mari
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bunikis, Ignas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Denker, Katrin
    Sickmann, Albert
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Benz, Roland
    DipA, a Pore-Forming Protein in the Outer Membrane of Lyme Disease Spirochetes Exhibits Specificity for the Permeation of Dicarboxylates2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 5, s. e36523-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lyme disease Borreliae are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography from Borrelia burgdorferi B31 and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borreliae. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a single-channel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl) were obtained among the 11 tested anions for oxaloacetate, 2-oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species.

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