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  • 1. Andersson, Ida
    et al.
    Simon, Melinda
    Lundkvist, Ake
    Nilsson, Mikael
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mirazimi, Ali
    Role of actin filaments in targeting of Crimean Congo hemorrhagic fever virus nucleocapsid protein to perinuclear regions of mammalian cells.2004In: J Med Virol, ISSN 0146-6615, Vol. 72, no 1, p. 83-93Article in journal (Refereed)
  • 2.
    Frithz-Lindsten, Elisabet
    et al.
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Holmström, Anna
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Jacobsson, Lars
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Soltani, Mehnam
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Olsson, Jan
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Functional conservation of the effector protein translocators PopB/YopB and PopD/YopD of Pseudomonas aeruginosa and Yersinia pseudotuberculosis.1998In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 29, no 5, p. 1155-1165Article in journal (Refereed)
    Abstract [en]

    Virulent Yersinia species cause systemic infections in rodents, and Y. pestis is highly pathogenic for humans. Pseudomonas aeruginosa, on the other hand, is an opportunistic pathogen, which normally infects only compromised individuals. Surprisingly, these pathogens both encode highly related contact-dependent secretion systems for the targeting of toxins into eukaryotic cells. In Yersinia, YopB and YopD direct the translocation of the secreted Yop effectors across the target cell membrane. In this study, we have analysed the function of the YopB and YopD homologues, PopB and PopD, encoded by P. aeruginosa. Expression of the pcrGVHpopBD operon in defined translocation-deficient mutants (yopB/yopD) of Yersinia resulted in complete complementation of the cell contact-dependent, YopE-induced cytotoxicity of Y. pseudotuberculosis on HeLa cells. We demonstrated that the complementation fully restored the ability of Y. pseudotuberculosis to translocate the effector molecules YopE and YopH into the HeLa cells. Similar to YopB, PopB induced a lytic effect on infected erythrocytes. The lytic activity induced by PopB could be prevented if the erythrocytes were infected in the presence of sugars larger than 3 nm in diameter, indicating that PopB induced a pore of similar size compared with that induced by YopB. Our findings show that the contact-dependent toxin-targeting mechanisms of Y. pseudotuberculosis and P. aeruginosa are conserved at the molecular level and that the translocator proteins are functionally interchangeable. Based on these similarities, we suggest that the translocation of toxins such as ExoS, ExoT and ExoU by P. aeruginosa across the eukaryotic cell membrane occurs via a pore induced by PopB.

  • 3.
    Holmström, Anna
    et al.
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Cherepanov, Peter
    Maier, Elke
    Nordfelth, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Åke
    LcrV is a channel size-determining component of the Yop effector translocon of Yersinia2001In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 39, no 3, p. 620-632Article in journal (Refereed)
    Abstract [en]

    Delivery of Yop effector proteins by pathogenic Yersinia across the eukaryotic cell membrane requires LcrV, YopB and YopD. These proteins were also required for channel formation in infected erythrocytes and, using different osmolytes, the contact‐dependent haemolysis assay was used to study channel size. Channels associated with LcrV were around 3 nm, whereas the homologous PcrV protein of Pseudomonas aeruginosa induced channels of around 2 nm in diameter. In lipid bilayer membranes, purified LcrV and PcrV induced a stepwise conductance increase of 3 nS and 1 nS, respectively, in 1 M KCl. The regions important for channel size were localized to amino acids 127–195 of LcrV and to amino acids 106–173 of PcrV. The size of the channel correlated with the ability to translocate Yop effectors into host cells. We suggest that LcrV is a size‐determining structural component of the Yop translocon.

  • 4.
    Holmström, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Oudin, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Department of Statistics.
    Nilsson, Karina
    Umeå University, Faculty of Social Sciences, Department of Sociology.
    Lindgren, Urban
    Umeå University, Faculty of Social Sciences, Department of Social and Economic Geography.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    SIMSAM-nätverket i Umeå strävar mot att bli ett framstående center för registerforskning som knyter samman barndomen med livslång hälsa och välfärd2011In: SVEPET - Medlemstidning för Svensk Epidemiologisk Förening (SVEP), ISSN 1101-4385, Vol. 29, no 3, p. 8-9Article in journal (Other academic)
    Abstract [sv]

    Vetenskapsrådets SIMSAM initiativ syftar till att stärka multidisciplinär registerforskning i Sverige. Inom SIMSAM-nätverket i Umeå arbetar vi tvärvetenskapligt med sikte på att utvecklas till ett center med excellens kring mikrodataforskning som knyter samman barndomen med livslång hälsa och välfärd. Just nu fokuserar vi på att få tillgång till sammanlänkade data från ett flertal nationella och regionala register för att komma vidare med vår planerade forskning. Dessutom har Umeå-nätverket nyligen fått i uppdrag att leda den nationella samordningen av SIMSAM initiativet.

  • 5.
    Holmström, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Petterson, Jonas
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Håkansson, Sebastian
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Tafazoli, Farideh
    Department of Medical Microbiology, Linköping University, S-581 85 Linköping, Sweden.
    Fällman, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Magnusson, Karl-Eric
    Department of Medical Microbiology, Linköping University, S-581 85 Linköping, Sweden.
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    Department of Microbiology, National Defence Research Establishment, S-901 82 Umeå, Sweden..
    YopK of Yersinia pseudotuberculosis controls translocation of Yop effectors across the eukaryotic cell membrane.1997In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 24, no 1, p. 73-91Article in journal (Refereed)
    Abstract [en]

    Introduction of anti-host factors into eukaryotic cells by extracellular bacteria is a strategy evolved by several Gram-negative pathogens. In these pathogens, the transport of virulence proteins across the bacterial membranes is governed by closely related type III secretion systems. For pathogenic Yersinia, the protein transport across the eukaryotic cell membrane occurs by a polarized mechanism requiring two secreted proteins, YopB and YopD. YopB was recently shown to induce the formation of a pore in the eukaryotic cell membrane, and through this pore, translocation of Yop effectors is believed to occur (Håkansson et al., 1996b). We have previously shown that YopK of Yersinia pseudotuberculosis is required for the development of a systemic infection in mice. Here, we have analysed the role of YopK in the virulence process in more detail. A yopK-mutant strain was found to induce a more rapid YopE-mediated cytotoxic response in HeLa cells as well as in MDCK-1 cells compared to the wild-type strain. We found that this was the result of a cell-contact-dependent increase in translocation of YopE into HeLa cells. In contrast, overexpression of YopK resulted in impaired translocation. In addition, we found that YopK also influenced the YopB-dependent lytic effect on sheep erythrocytes as well as on HeLa cells. A yopK-mutant strain showed a higher lytic activity and the induced pore was larger compared to the corresponding wild-type strain, whereas a strain overexpressing YopK reduced the lytic activity and the apparent pore size was smaller. The secreted YopK protein was found not to be translocated but, similar to YopB, localized to cell-associated bacteria during infection of HeLa cells. Based on these results, we propose a model where YopK controls the translocation of Yop effectors into eukaryotic cells.

  • 6.
    Holmström, Anna
    et al.
    Umeå University, Faculty of Medicine, Microbiology.
    Rosqvist, Roland
    Umeå University, Faculty of Medicine, Microbiology.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Microbiology.
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Microbiology.
    Virulence plasmid-encoded YopK is essential for Yersinia pseudotuberculosis to cause systemic infection in mice.1995In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 63, no 6, p. 2269-2276Article in journal (Refereed)
    Abstract [en]

    The virulence plasmid common to pathogenic Yersinia species encodes a number of secreted proteins denoted Yops (Yersinia outer proteins). Here, we identify and characterize a novel plasmid-encoded virulence determinant of Yersinia pseudotuberculosis, YopK. The yopK gene was found to be conserved among the three pathogenic Yersinia species and to be homologous to the previously described yopQ and yopK genes of Y. enterocolitica and Y. pestis, respectively. Similar to the other Yops, YopK expression and secretion were shown to be regulated by temperature and by the extracellular Ca2+ concentration; thus, yopK is part of the yop regulon. In addition, YopK secretion was mediated by the specific Yop secretion system. In Y. pseudotuberculosis, YopK was shown neither to have a role in this bacterium's ability to resist phagocytosis by macrophages nor to cause cytotoxicity in HeLa cells. YopK was, however, shown to be required for the bacterium to cause a systemic infection in both intraperitoneally and orally infected mice. Characterization of the infection kinetics showed that, similarly to the wild-type strain, the yopK mutant strain colonized and persisted in the Peyer's patches of orally infected mice. A yopE mutant which is impaired in cytotoxicity and in antiphagocytosis was, however, found to be rapidly cleared from these lymphoid organs. Neither the yopK nor the yopE mutant strain could overcome the primary host defense and reach the spleen. This finding implies that YopK acts at a different level during the infections process than the antiphagocytic YopE cytotoxin does.

  • 7.
    Johansson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindgren, Therese
    Lundström, Marlene
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bucht, Göran
    PCR-generated linear DNA fragments utilized as a hantavirus DNA vaccine2002In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 20, no 27-28, p. 3379-3388Article in journal (Refereed)
    Abstract [en]

    The field of DNA vaccines has grown rapidly, and since most such vaccines involve the inoculation of large circular DNA molecules previously propagated in bacteria, several inconveniences (e.g. the presence of antibiotic resistance genes, impurities from bacterial cultures or inefficient uptake of the large and bulky plasmid DNA molecules to the nucleus) are debated. In this study, we have explored the possibility of using smaller and more flexible PCR-generated linear DNA fragments instead. Phosphorothioate (PTO)-modified primers were used successfully to protect the PCR-generated DNA fragments from exonuclease degradation, and by using a nuclear localization signal-peptide to target the linear DNA to the nucleus the immune response against the encoded antigen was further improved. This approach was tested in cell culture using a sensitive reporter system and in vivo with DNA encoding the amino-terminus of the Puumala hantavirus nucleocapsid protein. Our results indicate that linear DNA fragments have a great potential as a genetic vaccine and phosphorothioate modification in combination with a nuclear localization signal peptide increase the stability and targets the linear DNA molecules to the nucleus resulting in an improved biological response examined both in vitro and in vivo.

  • 8.
    Johansson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olsson, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindgren, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Bucht, Göran
    FOI.
    Complete gene sequence of a human Puumala hantavirus isolate, Puumala Umeå/hu: sequence comparison and characterisation of encoded gene products.2004In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 105, no 2, p. 147-155Article in journal (Refereed)
    Abstract [en]

    Puumala virus is a member of the hantavirus genus in the Bunyaviridae family, and the major causative agent of haemorrhagic fever with renal syndrome in Europe. This study was conducted with a human Puumala virus isolate (PUUV Umeå/hu), and contains the determination of the first complete PUUV sequence from a human source. When the relationship to other Puumala viruses was analysed, a possible RNA segment exchange between two local strains of PUUV was noticed. Furthermore, the coding regions of PUUV Umeå/hu S- and M-segments were cloned, and a large set of gene products were expressed in mammalian cells. In addition, postulated N- and O-linked glycosylation sites in the two envelope proteins (Gn and Gc) were investigated individually by site-directed mutagenesis followed by gel-shift analysis. Our data demonstrate that N-linked glycosylation occurs at three sites in Gn (N142, N357 and N409), and at one site in Gc (N937). Also, one possible O-glycosylation site was identified in Gc (T985). We conclude that the diversity between different Puumala virus isolates is high, and consequently characterization of local PUUV isolates is important for clinical diagnostic work. Finally, the obtained results concerning the encoded gene products are of great importance for the design of new vaccines.

  • 9.
    Leary, Sophie E. C.
    et al.
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire, SP4 0JQ, U.K..
    Griffin, Kate F.
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire, SP4 0JQ, U.K..
    Galyov, Edouard E.
    Institute for Animal Health, Compton, Nr Newbury, Berkshire RG20 7NN, U.K..
    Hewer, Jason
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire, SP4 0JQ, U.K..
    Williamson, E. Diane
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire, SP4 0JQ, U.K..
    Holmström, Anna
    Department of Microbiology, Defence Research Establishment, S-901 87 Umeå, Sweden.
    Forsberg, Åke Forsberg
    Department of Microbiology, Defence Research Establishment, S-901 87 Umeå, Sweden.
    Titball, Richard W.
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire, SP4 0JQ, U.K..
    Yersinia outer proteins (YOPS) E, K and N are antigenic but non-protective compared to V antigen, in a murine model of bubonic plague1999In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 26, no 3, p. 159-169Article in journal (Refereed)
    Abstract [en]

    The pathogenic Yersiniae produce a range of virulence proteins, encoded by a 70 kb plasmid, which are essential for infection, and also form part of a contact-dependent virulence mechanism. One of these proteins, V antigen, has been shown to confer a high level of protection against parenteral infection with Y. pestis in murine models, and is considered to be a protective antigen. In this study, the protective efficacy of V antigen has been compared in the same model with that of other proteins (YopE, YopK and YopN), which are part of the contact-dependent virulence mechanism. Mice immunised with two intraperitoneal doses of V antigen or each of the Yops, administered with either Alhydrogel or interleukin-12, produced high antigen-specific serum IgG titres. As shown in previous studies, V+Alhydrogel was fully protective, and 5/5 mice survived a subcutaneous challenge with 90 or 9x10(3) LD50's of Y. pestis GB. In addition, these preliminary studies also showed that V+IL-12 was partially protective: 4/5 or 3/5 mice survived a challenge with 90 or 9x10(3) LD50's, respectively. In contrast, none of the mice immunised with the Yops survived the challenges, and there was no significant delay in the mean time to death compared to mice receiving a control protein. These results show that using two different vaccine regimens, Yops E, K and N, failed to elicit protective immune responses in a murine model of plague, whereas under the same conditions, V antigen was fully or partially protective.

  • 10. Lindgren, Lena
    et al.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Överby, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Regions of importance for interaction of puumala virus nucleocapsid subunits2006In: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 33, no 2, p. 169-174Article in journal (Refereed)
    Abstract [en]

    Puumala virus (PUUV) is a hantavirus that causes a mild form of hemorrhagic fever with renal syndrome in northern and central Europe, and in large parts of Russia. The nucleocapsid (N) protein encoded by hantaviruses plays an important role in the life-cycle of these viruses, and one important function for the N-protein is to oligomerize, surround and protect the viral RNAs. We have identified amino- and carboxy-terminal regions involved in PUUV N-N interactions, which comprise amino acids 100-120 and 330-405. Our findings strengthen the hypothesis that the amino-terminus of the N-protein of hantaviruses holds a more regulatory function regarding N-N interactions, while conserved residues in the carboxy-terminal region, F335 together with F336 and W392, in concert with Y388 and/or F400 seems to play a more critical role in the PUUV N-N formation. This study provides evidence that the amino-terminal regions involved in the N-N interaction of Puumala virus are similar to those reported for Seoul virus (SEOV) and to some extent Hantaan virus (HTNV), even though the identity between PUUV N and SEOV/HTNV N is markedly lower than between PUUV N and Tula virus (TULV) N or Sin Nombre virus (SNV) N.

  • 11.
    Lindkvist, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lahti, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lilliehöök, Bo
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Cross-reactive immune responses in mice after genetic vaccination with cDNA encoding hantavirus nucleocapsid proteins.2007In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 25, no 9, p. 1690-1699Article in journal (Refereed)
    Abstract [en]

    Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in about 150,000 individuals in Eurasia, and several hundred cases of hantavirus pulmonary syndrome (HPS) on the American continent annually. There is consequently a need for rapid diagnostics and effective prevention of hantaviral infections. In this study we have performed DNA-vaccination of mice with full-length genes encoding the immunogenic nucleocapsid protein (NP) of Puumala (PUUV), Seoul (SEOV) and Sin Nombre virus (SNV). The antibody reactivity towards the NPs, and deleted or truncated variants thereof, were studied to localise and investigate the major polyclonal B-cell epitopes. Our findings clearly show that the antibody reactivity in each immunised mouse is unique, not only in a quantitative respect (titers) but also in cross-reactivity and most likely also in the epitope specificity. Our experimental data in combination with B-cell prediction software indicate that strong homologous virus species specific and cross-reactive epitopes are located around amino acid residue 40 in the nucleocapsid proteins.

  • 12.
    Persson, Cathrine
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordfelth, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmström, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Håkansson, Sebastian
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Cell-surface-bound Yersinia translocate the protein tyrosine phosphatase YopH by a polarized mechanism into the target cell1995In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 18, no 1, p. 135-150Article in journal (Refereed)
    Abstract [en]

    YopH is translocated by cell-surface-bound bacteria through the plasma membrane to the cytosol of the HeLa cell. The transfer mechanism is contact dependent and polarizes the translocation to only occur at the contact zone between the bacterium and the target cell. More than 99% of the PTPase activity is associated with the HeLa cells. In contrast to the wild-type strain, the yopBD mutant cannot deliver YopH to the cytosol. Instead YopH is deposited in localized areas in the proximity of cell-associated bacteria. A yopN mutant secretes 40% of the total amount of YopH to the culture medium, suggesting a critical role of YopN in regulation of the polarized translocation. Evidence for a region in YopH important for its translocation through the plasma membrane of the target cell but not for secretion from the pathogen is provided.

  • 13.
    Pettersson, Jonas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Hill, Jim
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire SP4 OJQ, UK.
    Leary, Sophie
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire SP4 OJQ, UK.
    Frithz-Lindsten, Elisabet
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    von Euler-Matell, Anne
    Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden.
    Carlsson, Eva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Titball, Richard
    Biomedical Sciences Department, Defence Evaluation and Research Agency, Porton Down, Salisbury, Wiltshire SP4 OJQ, UK.
    Forsberg, Åke
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The V-antigen of Yersinia is surface exposed before target cell contact and involved in virulence protein translocation:  1999In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 32, no 5, p. 961-976Article in journal (Refereed)
    Abstract [en]

    Type III-mediated translocation of Yop effectors is an essential virulence mechanism of pathogenic Yersinia. LcrV is the only protein secreted by the type III secretion system that induces protective immunity. LcrV also plays a significant role in the regulation of Yop expression and secretion. The role of LcrV in the virulence process has, however, remained elusive on account of its pleiotropic effects. Here, we show that anti-LcrV antibodies can block the delivery of Yop effectors into the target cell cytosol. This argues strongly for a critical role of LcrV in the Yop translocation process. Additional evidence supporting this role was obtained by genetic analysis. LcrV was found to be present on the bacterial surface before the establishment of bacteria target cell contact. These findings suggest that LcrV serves an important role in the initiation of the translocation process and provides one possible explanation for the mechanism of LcrV-induced protective immunity.

  • 14. Revill, James
    et al.
    Candia Carnevali, M Daniela
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rath, Johannes
    Khan Shinwari, Zabta
    Mancini, Giulio M
    Lessons learned from implementing education on dual-use in Austria, Italy, Pakistan and Sweden2012In: Medicine, Conflict and Survival, ISSN 1362-3699, 1743-9396, Vol. 28, no 1, p. 31-44Article in journal (Refereed)
    Abstract [en]

    This paper provides insights into the achievements and challenges of implementing education on dual-use in four countries: Austria, Italy, Pakistan and Sweden. It draws attention to the different institutional mechanisms through which dual-use education may be introduced into academic curricula and some of the difficulties encountered in this process. It concludes that there is no ‘one size fits all’ approach to the implementation of dual-use education. Rather, initiatives must be tailored to suit the teaching traditions, geographical and historical context in which they are being delivered. However, a number of common principles and themes can be derived from all four cases. All these courses bring together a number of different topics that place ‘dual-use’ in the broader context of biosafety, biosecurity, ethics, law and the environment. The case studies suggest that success in this area depends largely on the leadership and commitment of individuals directly involved in teaching, who are active within the scientific community.

  • 15.
    Rietdorf, Jens
    et al.
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
    Ploubidou, Aspasia
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
    Reckmann, Inge
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany .
    Holmström, Anna
    European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
    Frischknecht, Friedrich
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
    Zettl, Markus
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
    Zimmermann, Timo
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
    Way, Michael
    Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
    Kinesin-dependent movement on microtubules precedes actin-based motility of vaccinia virus2001In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 3, no 11, p. 992-1000Article in journal (Refereed)
    Abstract [en]

    Vaccinia virus, a close relative of the causative agent of smallpox, exploits actin polymerization to enhance its cell-to-cell spread. We show that actin-based motility of vaccinia is initiated only at the plasma membrane and remains associated with it. There must therefore be another form of cytoplasmic viral transport, from the cell centre, where the virus replicates, to the periphery. Video analysis reveals that GFP-labelled intracellular enveloped virus particles (IEVs) move from their perinuclear site of assembly to the plasma membrane on microtubules. We show that the viral membrane protein A36R, which is essential for actin-based motility of vaccinia, is also involved in microtubule-mediated movement of IEVs. We further show that conventional kinesin is recruited to IEVs via the light chain TPR repeats and is required for microtubule-based motility of the virus. Vaccinia thus sequentially exploits the microtubule and actin cytoskeletons to enhance its cell-to-cell spread.

  • 16.
    Scaplehorn, Niki
    et al.
    European Molecular Biology Laboratory, Meyerhofstraße 1, D-69117 Heidelberg, Germany.
    Holmström, Anna
    European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
    Moreau, Violaine
    European Molecular Biology Laboratory, Meyerhofstraße 1, D-69117 Heidelberg, Germany.
    Frischknecht, Freddy
    European Molecular Biology Laboratory, Meyerhofstraße 1, D-69117 Heidelberg, Germany.
    Reckmann, Inge
    European Molecular Biology Laboratory, Meyerhofstraße 1, D-69117 Heidelberg, Germany.
    Way, Michael
    European Molecular Biology Laboratory, Meyerhofstraße 1, D-69117 Heidelberg, Germany.
    Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus2002In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 12, no 9, p. 740-745Article in journal (Refereed)
    Abstract [en]

    The Wiskott-Aldrich syndrome protein family member N-WASP is a key integrator of the multiple signalling pathways that regulate actin polymerization via the Arp2/3 complex. Our previous studies have shown that N-WASP is required for the actin-based motility of vaccinia virus and is recruited via Nck and WIP. We now show that Grb2 is an additional component of the vaccinia actin tail-forming complex. Recruitment of Nck and Grb2 to viral particles requires phosphorylation of tyrosine residues 112 and 132 of A36R, the vaccinia actin tail nucleator, respectively. The presence of Grb2 on the virus is also dependent on the polyproline-rich region of N-WASP. The Grb2 pathway alone is therefore unable to nucleate actin tails, as its recruitment requires the prior recruitment of N-WASP by Nck. However, Grb2 does play an important role in actin-based motility of vaccinia, as in its absence, the mean number of actin tails per cell is reduced 2.6-fold. Thus, both Nck and Grb2 act in a cooperative manner to stabilize and/or activate the vaccinia actin-nucleating complex. We suggest that such cooperativity between "primary" and "secondary" adaptor proteins is likely to be a general feature of receptor-mediated signalling.

  • 17.
    Tafazoli, Farideh
    et al.
    Division of Medical Microbiology, Department of Health and Environment, Linköping University, Linköping, Sweden.
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Forsberg, Åke
    Department of Microbiology, National Defence Research Establishment, Umeå, Sweden.
    Magnusson, Karl-Eric
    Division of Medical Microbiology, Department of Health and Environment, Linköping University, Linköping, Sweden.
    Apically exposed, tight junction-associated beta1-integrins allow binding and YopE-mediated perturbation of epithelial barriers by wild-type Yersinia bacteria2000In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 68, no 9, p. 5335-5343Article in journal (Refereed)
    Abstract [en]

    Using polarized epithelial cells, primarily MDCK-1, we assessed the mode of binding and effects on epithelial cell structure and permeability of Yersinia pseudotuberculosis yadA-deficient mutants. Initially, all bacteria except the invasin-deficient (inv) mutant adhered apically to the tight junction areas. These contact points of adjacent cells displayed beta1-integrins together with tight junction-associated ZO-1 and occludin proteins. Indeed, beta1-integrin expression was maximal in the tight junction area and then gradually decreased along the basolateral membranes. Wild-type bacteria also opened gradually the tight junction to paracellular permeation of different-sized markers, viz., 20-, 40-, and 70-kDa dextrans and 45-kDa ovalbumin, as well as to their own translocation between adjacent cells in intimate contact with beta1-integrins. The effects on the epithelial cells and their barrier properties could primarily be attributed to expression of the Yersinia outer membrane protein YopE, as the yopE mutant bound but caused no cytotoxicity. Moreover, the apical structure of filamentous actin (F-actin) was disturbed and tight junction-associated proteins (ZO-1 and occludin) were dispersed along the basolateral membranes. It is concluded that the Yersinia bacteria attach to beta1-integrins at tight junctions. Via this localized injection of YopE, they perturb the F-actin structure and distribution of proteins forming and regulating tight junctions. Thereby they promote paracellular translocation of bacteria and soluble compounds.

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