Umea Center for Microbial Research

Umeå, Sweden

Umea Center for Microbial Research

Umeå, Sweden
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Orikiiriza J.,Makerere University | Orikiiriza J.,Trinity College Dublin | Orikiiriza J.,Rwanda Military Hospital | Surowiec I.,Umeå University | And 11 more authors.
Metabolomics | Year: 2017

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. © 2017, The Author(s).

Surowiec I.,Umeå University | Orikiiriza J.,Makerere University | Orikiiriza J.,Trinity College Dublin | Karlsson E.,Umeå University | And 10 more authors.
Open Forum Infectious Diseases | Year: 2015

Background. Accuracy in malaria diagnosis and staging is vital to reduce mortality and post infectious sequelae. In this study, we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods. A group of 421 patients between 6 months and 6 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 20 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 2-component principal component analysis revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, 2 subgroups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusions. Metabolite signature profiling could be used both for decision support in disease staging and prognostication. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America.

Bui H.T.B.,Can Tho University | Ha Q.T.K.,Seoul National University | Oh W.K.,Seoul National University | Vo D.D.,Umeå University | And 7 more authors.
Tetrahedron Letters | Year: 2016

Twelve new 2-quinolizinylbenzimidazole and 2-naphthalylbenzimidazole derivatives with various 5- and 6-positioned substituents (aza, H, CH3, Cl, NO2, NH2, OCH3), have been synthesized in moderate to excellent yields via the condensation of 4-oxo-4H-quinolizinecarbaldehyde or naphthalenecarbaldehyde with substituted o-phenylenediamines, o-nitroaniline, and 2,3-pyridinediamine using sodium metabisulfite or sodium hydrosulfite under microwave irradiation. The new benzimidazole derivatives were screened for their cytotoxic activity against the human breast cancer cell line (MCF-7). The results showed on one hand that 2-(substituted quinolizinyl)-1H-benzimidazoles (12b-f) were less active (3-6 fold) than the positive control Tamoxifen (CC50 = 6.52 μM), and on the other hand, among the 2-(substituted naphthalyl)-1H-benzimidazoles series (13a-f), compounds 6,7,8-trimethoxy-3-(5-chloro-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13c) (CC50 = 7.48 μM) and 6,7,8-trimethoxy-3-(5-methoxy-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13f) (CC50 = 6.43 μM) were found to be as active as Tamoxifen. © 2016 Elsevier Ltd. All rights reserved.

Bui H.T.B.,Can Tho University | Vo D.D.,Umeå University | Vo D.D.,Umea Center for Microbial Research | Chau Y.N.T.,Vinh University | And 3 more authors.
Synthetic Communications | Year: 2015

A facile synthetic method for the construction of 2-substituted-4-oxo-4H-quinolizine-based core structure has been successfully developed. The synthesis made use of a one-pot Stobbe condensation followed by cyclization starting from the commercially available 2-pyridinecarbaldehyde. The structure of the formed 4-oxo-4H-quinolizine-2-carboxylate was fully confirmed by mass spectra, 1H NMR and 13C NMR, correlation spectrography, heteronuclear multiple bond correlation, and heteronuclear single quantum coherence (HSQC) spectra. The ethyl carboxylate moiety was then further functionalized via direct aminolysis by a range of amines to afford the corresponding 4-oxo-4H-quinolizine-2-carboxamides 4a-i in moderate to good yields. Copyright © Taylor & Francis Group, LLC.

Van Teeseling M.C.F.,Institute for Water and Wetland Research | Mesman R.J.,Institute for Water and Wetland Research | Kuru E.,Indiana University Bloomington | Espaillat A.,Umea Center for Microbial Research | And 6 more authors.
Nature Communications | Year: 2015

Planctomycetes are intriguing microorganisms that apparently lack peptidoglycan, a structure that controls the shape and integrity of almost all bacterial cells. Therefore, the planctomycetal cell envelope is considered exceptional and their cell plan uniquely compartmentalized. Anaerobic ammonium-oxidizing (anammox) Planctomycetes play a key role in the global nitrogen cycle by releasing fixed nitrogen back to the atmosphere as N2. Here using a complementary array of state-of-the-art techniques including continuous culturing, cryo-transmission electron microscopy, peptidoglycan-specific probes and muropeptide analysis, we show that the anammox bacterium Kuenenia stuttgartiensis contains peptidoglycan. On the basis of the thickness, composition and location of peptidoglycan in K. stuttgartiensis, we propose to redefine Planctomycetes as Gram-negative bacteria. Our results demonstrate that Planctomycetes are not an exception to the universal presence of peptidoglycan in bacteria. © 2015 Macmillan Publishers Limited. All rights reserved.

Andersson C.,Umeå University | Gripenland J.,Umeå University | Gripenland J.,Karolinska University Hospital | Johansson J.,Umeå University | Johansson J.,Umea Center for Microbial Research
Nature Protocols | Year: 2015

Microbial infections are a global health problem, particularly as microbes are continually developing resistance to antimicrobial treatments. An effective and reliable method for testing the virulence of different microbial pathogens is therefore a useful research tool. This protocol describes how the chicken embryo can be used as a trustworthy, inexpensive, ethically desirable and quickly accessible model to assess the virulence of the human bacterial pathogen Listeria monocytogenes, which can also be extended to other microbial pathogens. We provide a step-by-step protocol and figures and videos detailing the method, including egg handling, infection strategies, pathogenicity screening and isolation of infected organs. From the start of incubation of the fertilized eggs, the protocol takes <4 weeks to complete, with the infection part taking only 3 d. We discuss the appropriate controls to use and potential adjustments needed for adapting the protocol for other microbial pathogens. © 2015 Nature America, Inc. All rights reserved.

Sunduru N.,Umeå University | Sunduru N.,Umea Center for Microbial Research | Salin O.,Umeå University | Salin O.,Umea Center for Microbial Research | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2015

Abstract Discovery of new polypharmacological antibacterial agents with multiple modes of actions can be an alternative to combination therapy and also a possibility to slow development of antibiotic resistance. In support to this hypothesis, we synthesized 16 compounds by combining the pharmacophores of Chlamydia trachomatis inhibitors and inhibitors of type III secretion (T3S) in gram-negative bacteria. In this study we have developed salicylidene acylhydrazide sulfonamides (11c & 11d) as new antichlamydial agents that also inhibit T3S in Yersinia pseudotuberculosis. © 2015 The Authors.

Stylianou M.,Umeå University | Stylianou M.,Umea Center for Microbial Research | Uvell H.,Umea Center for Microbial Research | Uvell H.,Umeå University | And 8 more authors.
Journal of Biomolecular Screening | Year: 2015

Invasive mycoses have been increasing worldwide, with Candida spp. being the most prevalent fungal pathogen causing high morbidity and mortality in immunocompromised individuals. Only few antimycotics exist, often with severe side effects. Therefore, new antifungal drugs are urgently needed. Because the identification of antifungal compounds depends on fast and reliable assays, we present a new approach based on high-throughput image analysis to define cell morphology. Candida albicans and other fungi of the Candida clade switch between different growth morphologies, from budding yeast to filamentous hyphae. Yeasts are considered proliferative, whereas hyphae are required for invasion and dissemination. Thus, morphotype switching in many Candida spp. is connected to virulence and pathogenesis. It is, consequently, reasonable to presume that morphotype blockers interfere with the virulence, thereby preventing hazardous colonization. Our method efficiently differentiates yeast from hyphal cells using a combination of automated microscopy and image analysis. We selected the parameters length/width ratio and mean object shape to quantitatively discriminate yeasts and hyphae. Notably, Z' factor calculations for these parameters confirmed the suitability of our method for high-throughput screening. As a second stage, we determined cell viability to discriminate morphotype-switching inhibitors from those that are fungicidal. Thus, our method serves as a basis for the identification of candidates for next-generation antimycotics. © 2014 Society for Laboratory Automation and Screening.

Salomonsson E.N.,Swedish Defence Research Agency | Forslund A.-L.,Swedish Defence Research Agency | Forsberg A.,Umea Center for Microbial Research
Frontiers in Microbiology | Year: 2011

Francisella tularensis is a highly virulent intracellular human pathogen that is capable of rapid proliferation in the infected host. Mutants affected in intracellular survival and growth are highly attenuated which highlights the importance of the intracellular phase of the infection. Genomic analysis has revealed that Francisella encodes all genes required for expression of functional type IV pili (Tfp), and in this focused review we summarize recent findings regarding this system in the pathogenesis of tularemia. Tfp are dynamic adhesive structures that have been identified as major virulence determinants in several human pathogens, but it is not obvious what role these structures could have in an intracellular pathogen like Francisella. In the human pathogenic strains, genes required for secretion and assembly of Tfp and one pilin, PilA, have shown to be required for full virulence. Importantly, specific genetic differences have been identified between the different Francisella subspecies where in the most pathogenic type A variants all genes are intact while several Tfp genes are pseudogenes in the less pathogenic type B strains. This suggests that there has been a selection for expression of Tfp with different properties in the different subspecies. There is also a possibility that the genetic differences reflect adaptation to different environmental niches of the subspecies and plays a role in transmission of tularemia. This is also in line with recent findings where Tfp pilins are found to be glycosylated which could reflect a role for Tfp in the environment to promote survival and transmission. We are still far from understanding the role of Tfp in virulence and transmission of tularemia, but with the genomic information and genetic tools available we are in a good position to address these issues in the future. © 2011 Näslund Salomonsson,Forslund and Forsberg.

PubMed | Umea Center for Microbial Research
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to translocate virulence proteins into the cytosol of the target cells. T3SS-dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly translocated across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent translocation of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS-mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a different mechanism from the assumed single-step conduit model.

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