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  • 1.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Normark, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Björk, Rafael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Rietz, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Wolfraim, Lawrence A
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Signatures of T cells as correlates of immunity to Francisella tularensis2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. e32367-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tularemia or vaccination with the live vaccine strain (LVS) of Francisella tularensis confers long-lived cell-mediated immunity. We hypothesized that this immunity depends on polyfunctional memory T cells, i.e., CD4(+) and/or CD8(+) T cells with the capability to simultaneously express several functional markers. Multiparametric flow cytometry, measurement of secreted cytokines, and analysis of lymphocyte proliferation were used to characterize in vitro recall responses of peripheral blood mononuclear cells (PBMC) to killed F. tularensis antigens from the LVS or Schu S4 strains. PBMC responses were compared between individuals who had contracted tularemia, had been vaccinated, or had not been exposed to F. tularensis (naive). Significant differences were detected between either of the immune donor groups and naive individuals for secreted levels of IL-5, IL-6, IL-10, IL-12, IL-13, IFN-gamma, MCP-1, and MIP-1 beta. Expression of IFN-gamma, MIP-1 beta, and CD107a by CD4(+)CD45RO(+) or CD8(+) CD45RO(+) T cells correlated to antigen concentrations. In particular, IFN-gamma and MIP-1 beta strongly discriminated between immune and naive individuals. Only one cytokine, IL-6, discriminated between the two groups of immune individuals. Notably, IL-2- or TNF-alpha-secretion was low. Our results identify functional signatures of T cells that may serve as correlates of immunity and protection against F. tularensis.

  • 2.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rietz, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    House, Robert V
    Wolfraim, Lawrence A
    Tärnvik, Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Persistence of cell-mediated immunity three decades after vaccination with the live vaccine strain of Francisella tularensis2011Ingår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, nr 4, s. 974-980Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The efficacy of many vaccines against intracellular bacteria depends on the generation of cell-mediated immunity, but studies to determine the duration of immunity are usually confounded by re-exposure. The causative agent of tularemia, Francisella tularensis, is rare in most areas and, therefore, tularemia vaccination is an interesting model for studies of the longevity of vaccine-induced cell-mediated immunity. Here, lymphocyte proliferation and cytokine production in response to F. tularensis were assayed in two groups of 16 individuals, vaccinated 1-3 or 27-34 years previously. As compared to naïve individuals, vaccinees of both groups showed higher proliferative responses and, out of 17 cytokines assayed, higher levels of MIP-1β, IFN-γ, IL-10, and IL-5 in response to recall stimulation. The responses were very similar in the two groups of vaccinees. A statistical model was developed to predict the immune status of the individuals and by use of two parameters, proliferative responses and levels of IFN-γ, 91.1% of the individuals were correctly classified. Using flow cytometry analysis, we demonstrated that during recall stimulation, expression of IFN-γ by CD4(+) CCR7(+) , CD4(+) CD62L(+) , CD8(+) CCR7(+) , and CD8(+) CD62L(+) cells significantly increased in samples from vaccinated donors. In conclusion, cell-mediated immunity was found to persist three decades after tularemia vaccination without evidence of decline.

  • 3. Ertürk-Hasdemir, Deniz
    et al.
    Broemer, Meike
    Leulier, Francois
    Lane, William S
    Paquette, Nicholas
    Hwang, Daye
    Kim, Chan-Hee
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Meier, Pascal
    Silverman, Neal
    Two roles for the Drosophila IKK complex in the activation of Relish and the induction of antimicrobial peptide genes2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 24, s. 9779-9784Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Drosophila NF-kappa B transcription factor Relish is an essential regulator of antimicrobial peptide gene induction after Gram-negative bacterial infection. Relish is a bipartite NF-kappa B precursor protein, with an N-terminal Rel homology domain and a C-terminal I kappa B-like domain, similar to mammalian p100 and p105. Unlike these mammalian homologs, Relish is endoproteolytically cleaved after infection, allowing the N-terminal NF-kappa B module to translocate to the nucleus. Signal-dependent activation of Relish, including cleavage, requires both the Drosophila I kappa B kinase (IKK) and death-related ced-3/Nedd2-like protein (DREDD), the Drosophila caspase-8 like protease. In this report, we show that the IKK complex controls Relish by direct phosphorylation on serines 528 and 529. Surprisingly, these phosphorylation sites are not required for Relish cleavage, nuclear translocation, or DNA binding. Instead they are critical for recruitment of RNA polymerase II and antimicrobial peptide gene induction, whereas IKK functions noncatalytically to support Dredd-mediated cleavage of Relish.

  • 4.
    Kinsman, John
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Stöven, Svenja
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Elgh, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Murillo, Pilar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Sulzner, Michael
    Good practices and challenges in addressing poliomyelitis and measles in the European Union2018Ingår i: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 28, nr 4, s. 730-734Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: All European Union (EU) and European Economic Area (EEA) Member States have pledged to ensure political commitment towards sustaining the region's poliomyelitis-free status and eliminating measles. However, there remain significant gaps between policy and practice in many countries. This article reports on an assessment conducted for the European Commission that aimed to support improvements in preparedness and response to poliomyelitis and measles in Europe.

    Methods: A documentary review was complemented by qualitative interviews with professionals working in International and EU agencies, and in at-risk or recently affected EU/EEA Member States (six each for poliomyelitis and measles). Twenty-six interviews were conducted on poliomyelitis and 24 on measles; the data were subjected to thematic analysis. Preliminary findings were then discussed at a Consensus Workshop with 22 of the interviewees and eight other experts.

    Results: Generic or disease-specific plans exist in the participating countries and cross-border communications during outbreaks were generally reported as satisfactory. However, surveillance systems are of uneven quality, and clinical expertise for the two diseases is limited by a lack of experience. Serious breaches of protocol have recently been reported from companies producing poliomyelitis vaccines, and vaccine coverage rates for both diseases were also sub-optimal. A set of suggested good practices to address these and other challenges is presented.

    Conclusions: Poliomyelitis and measles should be brought fully onto the policy agendas of all EU/EEA Member States, and adequate resources provided to address them. Each country must abide by the relevant commitments that they have already made.

  • 5. Kleino, Anni
    et al.
    Valanne, Susanna
    Ulvila, Johanna
    Kallio, Jenni
    Myllymäki, Henna
    Enwald, Heidi
    Stöven, Svenja
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Poidevin, Mickael
    Ueda, Ryu
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Lemaitre, Bruno
    Rämet, Mika
    Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway.2005Ingår i: EMBO J, ISSN 0261-4189, Vol. 24, nr 19, s. 3423-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Imd signaling cascade, similar to the mammalian TNF-receptor pathway, controls antimicrobial peptide expression in Drosophila. We performed a large-scale RNAi screen to identify novel components of the Imd pathway in Drosophila S2 cells. In all, 6713 dsRNAs from an S2 cell-derived cDNA library were analyzed for their effect on Attacin promoter activity in response to Escherichia coli. We identified seven gene products required for the Attacin response in vitro, including two novel Imd pathway components: inhibitor of apoptosis 2 (Iap2) and transforming growth factor-activated kinase 1 (TAK1)-binding protein (TAB). Iap2 is required for antimicrobial peptide response also by the fat body in vivo. Both these factors function downstream of Imd. Neither TAB nor Iap2 is required for Relish cleavage, but may be involved in Relish nuclear localization in vitro, suggesting a novel mode of regulation of the Imd pathway. Our results show that an RNAi-based approach is suitable to identify genes in conserved signaling cascades.

  • 6. Lindmark, H
    et al.
    Johansson, K C
    Stöven, Svenja
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Engström, Ylva
    Söderhäll, Kenneth
    Enteric bacteria counteract lipopolysaccharide induction of antimicrobial peptide genes.2001Ingår i: J Immunol, ISSN 0022-1767, Vol. 167, nr 12, s. 6920-3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The humoral immunity of Drosophila involves the production of antimicrobial peptides, which are induced by evolutionary conserved microbial molecules, like LPS. By using Drosophila mbn-2 cells, we found that live bacteria, including E. coli, Salmonella typhimurium, Erwinia carotovora, and Pseudomonas aeruginosa, prevented LPS from inducing antimicrobial peptide genes, while Micrococcus luteus and Streptococcus equi did not. The inhibitory effect was seen at bacterial levels from 20 per mbn-2 cell, while antimicrobial peptides were induced at lower bacterial concentrations (< or =2 bacteria per cell) also in the absence of added LPS. Gel shift experiment suggests that the inhibitory effect is upstream or at the level of the activation of the transcription factor Relish, a member of the NF-kappaB/Rel family. The bacteria have to be in physical contact with the cells, but not phagocytosed, to prevent LPS induction. Interestingly, the inhibiting mechanism is, at least for E. coli, independent of the type III secretion system, indicating that the inhibitory mechanism is unrelated to the one earlier described for YopJ from Yersinia.

  • 7.
    Plamboeck, Agneta H.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Stöven, Svenja
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Davidson, Raquel Duarte
    Fykse, Else-Marie
    Griffiths, Mark
    Nieuwenhuizen, Maarten
    Rivier, Cedric
    van der Schans, Marcel
    Laboratory analysis of CBRN-substances: Stakeholder networks as clue to higher CBRN resilience in Europe2016Ingår i: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 85, nr Part B, s. 2-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The threat of terrorists using CBRN agents continues to pose a risk of mass casualties and severe disruption of societal functions in Europe. Standardisation of crisis management activities is one important step towards effective national and international interoperability and increased resilience. Understanding which CBRN agents are involved in an incident is vital for appropriate response measures. We applied a system's view on the process of CBRN sample analysis and see three discrete applications; Immediate incident response, Forensics, Post incident monitoring. Together with laboratory experts and policy makers from across Europe we identified needs for quality assurance measures in these three areas. Here, we suggest various harmonisation activities that can facilitate interoperability between all stakeholders concerned with CBRN sample analysis. Foremost, we recommend purpose-oriented laboratory networks, but also minimum performance requirements for First Responders' detection and sampling capabilities, best practices for sample transport and documentation.

  • 8. Silverman, N
    et al.
    Zhou, R
    Stöven, Svenja
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Pandey, N
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Maniatis, T
    A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity.2000Ingår i: Genes Dev, ISSN 0890-9369, Vol. 14, nr 19, s. 2461-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes. In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro. Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish. The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes. Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development. Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway.

  • 9.
    Stöven, Svenja
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Ando, Istvan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Kadalayil, Latha
    Engström, Ylva
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Activation of the Drosophila NF-kappaB factor Relish by rapid endoproteolytic cleavage.2000Ingår i: EMBO Rep, ISSN 1469-221X, Vol. 1, nr 4, s. 347-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Rel/NF-kappaB transcription factor Relish plays a key role in the humoral immune response in Drosophila. We now find that activation of this innate immune response is preceded by rapid proteolytic cleavage of Relish into two parts. An N-terminal fragment, containing the DNA-binding Rel homology domain, translocates to the nucleus where it binds to the promoter of the Cecropin A1 gene and probably to the promoters of other antimicrobial peptide genes. The C-terminal IkappaB-like fragment remains in the cytoplasm. This endoproteolytic cleavage does not involve the proteasome, requires the DREDD caspase, and is different from previously described mechanisms for Rel factor activation.

  • 10.
    Stöven, Svenja
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Bäcklund, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Sahovic, Dzenan
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statsvetenskapliga institutionen.
    Ethics Issues Management Workshop: PRACTICE project deliverable 1.32013Rapport (Övrigt vetenskapligt)
  • 11.
    Stöven, Svenja
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Silverman, Neal
    Junell, Anna
    Hedengren-Olcott, Marika
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Erturk, Deniz
    Engstrom, Ylva
    Maniatis, Tom
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Caspase-mediated processing of the Drosophila NF-kappaB factor Relish.2003Ingår i: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 100, nr 10, s. 5991-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The NF-kappaB-like transcription factor Relish plays a central role in the innate immune response of Drosophila. Unlike other NF-kappaB proteins, Relish is activated by endoproteolytic cleavage to generate a DNA-binding Rel homology domain and a stable IkappaB-like fragment. This signal-induced endoproteolysis requires the activity of several gene products, including the IkappaB kinase complex and the caspase Dredd. Here we used mutational analysis and protein microsequencing to demonstrate that a caspase target site, located in the linker region between the Rel and the IkappaB-like domain, is the site of signal-dependent cleavage. We also show physical interaction between Relish and Dredd, suggesting that Dredd indeed is the Relish endoprotease. In addition to the caspase target site, the C-terminal 107 aa of Relish are required for endoproteolysis and signal-dependent phosphorylation by the Drosophila IkappaB kinase beta. Finally, an N-terminal serine-rich region in Relish and the PEST domain were found to negatively regulate Relish activation.

  • 12.
    Vonkavaara, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Pavel, Shaikh Terkis Islam
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hölzl, Kathrin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Nordfelth, Roland
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Stöven, Svenja
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Europeiska CBRNE-centret.
    Francisella is sensitive to insect antimicrobial peptides2013Ingår i: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 5, nr 1, s. 50-59Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Francisella tularensis causes the zoonotic disease tularemia. Arthropod vectors are important transmission routes for the disease, although it is not known how Francisella survives the efficient arthropod immune response. Here, we used Drosophila melanogaster as a model host for Francisella infections and investigated whether the bacteria are resistant to insect humoral immune responses, in particular to the antimicrobial peptides (AMPs) secreted into the insect hemolymph. Moreover, we asked to which extent such resistance might depend on LPS structure and surface characteristics of the bacteria. We analyzed F. novicida mutant strains in genes, directly or indirectly involved in specific steps of LPS biosynthesis, for virulence in wildtype and Relish E20 immune deficient flies, and tested selected mutants for sensitivity to AMPs in vitro. We demonstrate that Francisella is sensitive to specific fly AMPs, i.e. Attacin, Cecropin, Drosocin and Drosomycin. Furthermore, six bacterial genes, kpsF, manB, lpxF, slt, tolA and pal, were found to be required for resistance to Relish-dependent immune responses, illustrating the importance of structural details of Francisella lipid A and Kdo core for interactions with AMPs. Interestingly, a more negative surface charge and lack of O-antigen did not render mutant bacteria more sensitive to cationic AMPs and attenuated virulence in flies.

  • 13.
    Vonkavaara, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    The role of JNK signaling in Francisella tularensis infection of Drosophila melanogasterManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The causative agent of tularemia, Francisella tularensis, inhibits immune signaling pathways during infection and thus reduces the production of proinflammatory cytokines. NF-kB and MAPK pathways are initially activated, but subsequently down-regulated in macrophages. The mechanism(s) of inhibition, or which host proteins that F. tularensis interacts with are not known. Here, we have used Drosophila melanogaster as a genetically amendable model host to study the interaction between F. tularensis LVS and host immune signaling. We found that similar as in mammalian macrophages, LVS inhibits the JNK pathway in flies. LVS interferes with the JNK pathway upstream or at the same level as the JNKK Hemipterous. Expression of an activated Hemipterous in fly macrophage-like cells had a protective effect on fly survival, while inhibiting the JNK pathway in the fly fat body, an important immune tissue, had no effect on fly survival.

  • 14.
    Vonkavaara, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Telepnev, Maxim V
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Drosophila melanogaster as a model for elucidating the pathogenicity of Francisella tularensis2008Ingår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, nr 6, s. 1327-1338Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Drosophila melanogaster is a widely used model organism for research on innate immunity and serves as an experimental model for infectious diseases. The aetiological agent of the zoonotic disease tularaemia, Francisella tularensis, can be transmitted by ticks and mosquitoes and Drosophila might be a useful, genetically amenable model host to elucidate the interactions between the bacterium and its arthropod vectors. We found that the live vaccine strain of F. tularensis was phagocytosed by Drosophila and multiplied in fly haemocytes in vitro and in vivo. Bacteria injected into flies resided both inside haemocytes and extracellularly in the open circulatory system. A continuous activation of the humoral immune response, i.e. production of antimicrobial peptides under control of the imd/Relish signalling pathway, was observed and it may have contributed to the relative resistance to F. tularensis as flies defective in the imd/Relish pathway died rapidly. Importantly, bacterial strains deficient for genes of the F. tularensis intracellular growth locus or the macrophage growth locus were attenuated in D. melanogaster. Our results demonstrate that D. melanogaster is a suitable model for the analysis of interactions between F. tularensis and its arthropod hosts and that it can also be used to identify F. tularensis virulence factors relevant for mammalian hosts.

  • 15.
    Wiklund, Magda-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Steinert, Stefanie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Junell, Anna
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    The N-terminal half of the Drosophila Rel/NF-kappaB factor Relish, REL-68, constitutively activates transcription of specific Relish target genes2009Ingår i: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 33, nr 5, s. 690-696Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Rel/NF-kappaB transcription factor Relish is a major regulator of the antimicrobial response in Drosophila. Upon immune challenge, Relish is cleaved to generate two fragments, the DNA-binding transcription factor REL-68 and the IkappaB-like REL-49. Using transgenic fly strains we show here that overexpression of REL-68 separately from REL-49 is sufficient to activate strong constitutive transcription of the Diptericin gene, but little constitutive or inducible transcription of Attacin and Cecropin, two other Relish target genes. Their transcription may therefore require additional modifications of Relish. However, phosphorylation of the conserved serine residue S431 is not involved in such modifications. This is unlike p65 and Dorsal, which are modulated by phosphorylation at their homologous site. In contrast to other IkappaB proteins, overexpression of REL-49 had no inhibitory effect on Relish-dependent transcription. Instead, we propose that the C-terminal IkappaB-like domain executes a scaffolding and recruiting function for full activation of Relish.

  • 16.
    Åhlund, Monika K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Directed screen of Francisella novicida virulence determinants using Drosophila melanogaster2010Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, nr 7, s. 3118-3128Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Francisella tularensis is a highly virulent, facultative intracellular human pathogen whose virulence mechanisms are not well understood. Occasional outbreaks of tularemia and the potential use of F. tularensis as a bioterrorist agent warrant better knowledge about the pathogenicity of this bacterium. Thus far, genome-wide in vivo screens for virulence factors have been performed in mice, all however restricted by the necessity to apply competition-based, negative-selection assays. We wanted to individually evaluate putative virulence determinants suggested by such assays and performed directed screening of 249 F. novicida transposon insertion mutants by using survival of infected fruit flies as a measure of bacterial virulence. Some 20% of the genes tested were required for normal virulence in flies; most of these had not previously been investigated in detail in vitro or in vivo. We further characterized their involvement in bacterial proliferation and pathogenicity in flies and in mouse macrophages. Hierarchical cluster analysis of mutant phenotypes indicated a functional linkage between clustered genes. One cluster grouped all but four genes of the Francisella pathogenicity island and other loci required for intracellular survival. We also identified genes involved in adaptation to oxidative stress and genes which might induce host energy wasting. Several genes related to type IV pilus formation demonstrated hypervirulent mutant phenotypes. Collectively, the data demonstrate that the bacteria in part use similar virulence mechanisms in mammals as in Drosophila melanogaster but that a considerable proportion of the virulence factors active in mammals are dispensable for pathogenicity in the insect model.

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