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  • 1.
    Billker, Oliver
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    CRISPRing the elephant in the room2018Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 24, nr 6, s. 754-755Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The importance of guanylyl-cyclases (GCs) in apicomplexa has remained elusive due to the large size of the genes. Two recent studies, including Brown and Sibley, 2018 in this issue of Cell Host & Microbe, make elegant use of genome editing with CRISPR-Cas9 to characterize roles of GCs in Toxoplasma and Plasmodium.

  • 2. Billker, Oliver
    et al.
    Lourido, Sebastian
    Sibley, L David
    Calcium-dependent signaling and kinases in apicomplexan parasites2009Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 5, nr 6, s. 612-622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Calcium controls many critical events in the complex life cycles of apicomplexan parasites including protein secretion, motility, and development. Calcium levels are normally tightly regulated and rapid release of calcium into the cytosol activates a family of calcium-dependent protein kinases (CDPKs), which are normally characteristic of plants. CDPKs present in apicomplexans have acquired a number of unique domain structures likely reflecting their diverse functions. Calcium regulation in parasites is closely linked to signaling by cyclic nucleotides and their associated kinases. This Review summarizes the pivotal roles that calcium- and cyclic nucleotide-dependent kinases play in unique aspects of parasite biology.

  • 3.
    Billker, Oliver
    et al.
    Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
    Rayner, Julian C.
    Calcium Builds Strong Host-Parasite Interactions2015Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 18, nr 1, s. 9-10Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Apicomplexan parasite invasion of host cells is a multistep process, requiring coordinated events. In this issue of Cell Host & Microbe, Paul et al. (2015) and Philip and Waters (2015) leverage experimental genetics to show that the calcium-regulated protein phosphatase, calcinuerin, regulates invasion in multiple parasite species.

  • 4.
    Blomgran, Robert
    et al.
    New York University School of Medicine.
    Desvignes, Ludovic
    New York University School of Medicine.
    Briken, Volker
    University of Maryland.
    Ernst, Joel D
    New York University School of Medicine.
    Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells2012Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 11, nr 1, s. 81-90Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.

  • 5.
    Bugaytsova, Jeanna A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björnham, Oscar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Swedish Defence Research Agency, 906 21 Umeå, Sweden.
    Chernov, Yevgen A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gideonsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Henriksson, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mendez, Melissa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mahdavi, Jafar
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. School of Life Sciences, CBS, University of Nottingham, NG7 2RD Nottingham, UK.
    Shevtsova, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ilver, Dag
    Moonens, Kristof
    Quintana-Hayashi, Macarena P.
    Moskalenko, Roman
    Aisenbrey, Christopher
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bylund, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schmidt, Alexej
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Åberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Koeniger, Verena
    Vikström, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rakhimova, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ögren, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Liu, Hui
    Goldman, Matthew D.
    Whitmire, Jeannette M.
    Åden, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Younson, Justine
    Kelly, Charles G.
    Gilman, Robert H.
    Chowdhury, Abhijit
    Mukhopadhyay, Asish K.
    Nair, G. Balakrish
    Papadakos, Konstantinos S.
    Martinez-Gonzalez, Beatriz
    Sgouras, Dionyssios N.
    Engstrand, Lars
    Unemo, Magnus
    Danielsson, Dan
    Suerbaum, Sebastian
    Oscarson, Stefan
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holgersson, Jan
    Esberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Strömberg, Nicklas
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Landström, Maréne
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Eldridge, Angela M.
    Chromy, Brett A.
    Hansen, Lori M.
    Solnick, Jay V.
    Linden, Sara K.
    Haas, Rainer
    Dubois, Andre
    Merrell, D. Scott
    Schedin, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Remaut, Han
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berg, Douglas E.
    Boren, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence2017Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, nr 3, s. 376-389Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

  • 6.
    Bugaytsova, Jeanna A.
    et al.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Björnham, Oscar
    Department of Applied Physics and Electronics, Umeå University, Umeå, Sweden; Swedish Defence Research Agency, Umeå, Sweden.
    Chernov, Yevgen A.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Gideonsson, Pär
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Henriksson, Sara
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; Umeå Core Facil Electron Microscopy UCEM, Umeå University, Umeå, Sweden.
    Mendez, Melissa
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Sjöström, Rolf
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Mahdavi, Jafar
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; School of Life Sciences, CBS, University of Nottingham, Nottingham, United Kingdom.
    Shevtsova, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Ilver, Dag
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Acreo Swedish ICT AB, Gothenburg, Sweden.
    Moonens, Kristof
    Structural and Molecular Microbiology, VIB Department of Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium .
    Quintana-Hayashi, Macarena P.
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Moskalenko, Roman
    Department of Pathology, Medical Institute, Sumy State University, Sumy, Ukraine.
    Aisenbrey, Christopher
    Department of Chemistry, Umeå University, Umeå, Sweden; Inst Chim, Univ Strasbourg, Strasbourg, France.
    Bylund, Göran
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Schmidt, Alexej
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; Dept Med Biosci, Umeå Univ, Umeå, Sweden.
    Åberg, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Brännström, Kristoffer
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Königer, Verena
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany.
    Vikström, Susanne
    Department of Medical Biochemistry and Biophysics & Faculty Science and Technology, Umeå University, Umeå, Sweden.
    Rakhimova, Lena
    Department of Chemistry, Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Hofer, Anders
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Ögren, Johan
    Department of Odontology, Umeå University, Umeå, Sweden.
    Liu, Hui
    Department of Medicine, USUHS, Bethesda MD, United States.
    Goldman, Matthew D.
    Department of Pediatrics, USUHS, Bethesda MD, United States.
    Whitmire, Jeannette M.
    Department of Microbiology and Immunology, USUHS, Bethesda MD, United States.
    Ådén, Jörgen
    Department of Chemistry, Umeå University, Umeå, Sweden.
    Younson, Justine
    Dental Institute, King's College London, London, United Kingdom.
    Kelly, Charles G.
    Dental Institute, King's College London, London, United Kingdom.
    Gilman, Robert H.
    Department of International Health, John Hopkins School of Public Health, Baltimore MD, United States.
    Chowdhury, Abhijit
    Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India.
    Mukhopadhyay, Asish K.
    Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
    Nair, G. Balakrish
    Translational Health Science and Technology Institute, Haryana, India; WHO Research Policy & Cooperation Unit, New Delhi, India.
    Papadakos, Konstantinos S.
    Hellenic Pasteur Institute, Athens, Greece; Department of Translational Medicine, Wallenberg Lab, Lund University, Malmö, Sweden.
    Martinez-Gonzalez, Beatriz
    Hellenic Pasteur Institute, Athens, Greece.
    Sgouras, Dionyssios N.
    Hellenic Pasteur Institute, Athens, Greece.
    Engstrand, Lars
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Sci Life Lab, Solna, Sweden.
    Unemo, Magnus
    Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Danielsson, Dan
    Region Örebro län. Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Suerbaum, Sebastian
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany ; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany; German Center for Infection Research (DZIF), Munich, Germany.
    Oscarson, Stefan
    Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin, Ireland.
    Morozova-Roche, Ludmilla A.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Olofsson, Anders
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Gröbner, Gerhard
    Department of Chemistry, Umeå University, Umeå, Sweden.
    Holgersson, Jan
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Esberg, Anders
    Department of Odontology, Umeå University, Umeå, Sweden.
    Strömberg, Nicklas
    Department of Odontology, Umeå University, Umeå, Sweden.
    Landström, Maréne
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany.
    Eldridge, Angela M.
    Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento CA, United States; Genentech Inc, Vacaville CA, USA.
    Chromy, Brett A.
    Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento CA, United States ; Singulex Inc, Alameda CA, USA.
    Hansen, Lori M.
    Departments of Medical Microbiology and Immunology, Center for Comparative Medicine, University of California Davis, Davis CA, United States.
    Solnick, Jay V.
    Departments of Medical Microbiology and Immunology, Center for Comparative Medicine, University of California, Davis CA, United States; California National Primate Research Center, University of California, Davis CA, USA .
    Lindén, Sara K.
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Haas, Rainer
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany; German Center for Infection Research (DZIF), Munich, Germany .
    Dubois, Andre
    Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda MD, United States.
    Merrell, D. Scott
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda MD, United States.
    Schedin, Staffan
    Department of Applied Physics and Electronics, Umeå University, Umeå, Sweden.
    Remaut, Han
    Structural and Molecular Microbiology, VIB Department of Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium .
    Arnqvist, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Berg, Douglas E.
    Department of Medicine, University of California San Diego, La Jolla CA, United States.
    Borén, Thomas
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence2017Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, nr 3, s. 376-389, artikel-id S1931-3128(17)30075-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

  • 7.
    Bäckhed, Fredrik
    et al.
    The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden & Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Roswall, Josefine
    Department of Pediatrics, Hallands Hospital Halmstad, Halmstad, Sweden & Göteborg Paediatric Growth Research Center, Department of Paediatrics, the University of Gothenburg, Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Peng, Yangqing
    BGI-Shenzhen, Shenzhen, China.
    Feng, Qiang
    BGI-Shenzhen, Shenzhen, China &Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Jia, Huijue
    BGI-Shenzhen, Shenzhen, China.
    Kovatcheva-Datchary, Petia
    The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Li, Yin
    BGI-Shenzhen, Shenzhen, China.
    Xia, Yan
    BGI-Shenzhen, Shenzhen, China.
    Xie, Hailiang
    BGI-Shenzhen, Shenzhen, China.
    Zhong, Huanzi
    BGI-Shenzhen, Shenzhen, China.
    Khan, Muhammad Tanweer
    The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Zhang, Jianfeng
    BGI-Shenzhen, Shenzhen, China.
    Li, Junhua
    BGI-Shenzhen, Shenzhen, China.
    Xiao, Liang
    BGI-Shenzhen, Shenzhen, China.
    Al-Aama, Jumana
    BGI-Shenzhen, Shenzhen, China & Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Saudi Arabia.
    Zhang, Dongya
    BGI-Shenzhen, Shenzhen, China.
    Lee, Ying Shiuan
    The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Kotowska, Dorota
    Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Colding, Camilla
    Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Tremaroli, Valentina
    The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Yin, Ye
    BGI-Shenzhen, Shenzhen, China.
    Bergman, Stefan
    Göteborg Paediatric Growth Research Center, Department of Paediatrics, the University of Gothenburg, Queen Silvia Children’s Hospital, Gothenburg & Research and Development Center Spenshult, Oskarström, Sweden.
    Xu, Xun
    BGI-Shenzhen, Shenzhen, China.
    Madsen, Lise
    Department of Biology, University of Copenhagen, Copenhagen, Denmark & National Institute of Nutrition and Seafood Research, Bergen, Norway.
    Kristiansen, Karsten
    BGI-Shenzhen, Shenzhen, China & Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Dahlgren, Jovanna
    Göteborg Paediatric Growth Research Center, Department of Paediatrics, the University of Gothenburg, Queen Silvia Children’s Hospital, Gothenburg & .
    Wang, Jun
    BGI-Shenzhen, Shenzhen, China, Department of Biology, University of Copenhagen, Copenhagen, Denmark, Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Saudi Arabia, Macau University of Science and Technology, Avenida Wai long, Taipa, China & Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong.
    Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life2015Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 17, nr 5, s. 690-703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life. © 2015 Elsevier Inc.

  • 8. Coppi, Alida
    et al.
    Tewari, Rita
    Bishop, Joseph R
    Bennett, Brandy L
    Lawrence, Roger
    Esko, Jeffrey D
    Billker, Oliver
    Division of Cell and Molecular Biology, Imperial College London, UK.
    Sinnis, Photini
    Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells2007Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 2, nr 5, s. 316-327Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malaria infection is initiated when Anopheles mosquitoes inject Plasmodium sporozoites into the skin. Sporozoites subsequently reach the liver, invading and developing within hepatocytes. Sporozoites contact and traverse many cell types as they migrate from skin to liver; however, the mechanism by which they switch from a migratory mode to an invasive mode is unclear. Here, we show that sporozoites of the rodent malaria parasite Plasmodium berghei use the sulfation level of host heparan sulfate proteoglycans (HSPGs) to navigate within the mammalian host. Sporozoites migrate through cells expressing low-sulfated HSPGs, such as those in skin and endothelium, while highly sulfated HSPGs of hepatocytes activate sporozoites for invasion. A calcium-dependent protein kinase is critical for the switch to an invasive phenotype, a process accompanied by proteolytic cleavage of the sporozoite's major surface protein. These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry.

  • 9. Dolowschiak, Tamas
    et al.
    Mueller, Anna Angelika
    Pisan, Lynn Joanna
    Feigelman, Rounak
    Felmy, Boas
    Sellin, Mikael Erik
    Namineni, Sukumar
    Nguyen, Bidong Dinh
    Wotzka, Sandra Yvonne
    Heikenwalder, Mathias
    von Mering, Christian
    Mueller, Christoph
    Hardt, Wolf-Dietrich
    IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection.2016Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 20, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (ψ50: ∼48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-γ (IFN-γ)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-γ production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1β, TNF, and iNOS. Additionally, sustained IFN-γ fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIβ. These findings reveal a role for IFN-γ in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.

  • 10. Gomes, Ana Rita
    et al.
    Bushell, Ellen
    Schwach, Frank
    Girling, Gareth
    Anar, Burcu
    Quail, Michael A.
    Herd, Colin
    Pfander, Claudia
    Modrzynska, Katarzyna
    Rayner, Julian C.
    Billker, Oliver
    Wellcome Trust Sanger Institute, Hinxton Cambridge CB10 1SA, UK.
    A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite2015Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 17, nr 3, s. 404-413Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.

  • 11.
    Herp, Simone
    et al.
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany.
    Brugiroux, Sandrine
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany;Univ Clermont Auvergne, Microbes Intestine Inflammat & Host Susceptibil, INRA 2018, UMR 1071 Inserm,USC, Clermont Ferrand, France.
    Garzetti, Debora
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany;German Ctr Infect Res DZIF, Partner Site LMU Munich, D-80336 Munich, Germany.
    Ring, Diana
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany;German Ctr Infect Res DZIF, Partner Site LMU Munich, D-80336 Munich, Germany.
    Jochum, Lara M.
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany.
    Beutler, Markus
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany.
    Eberl, Claudia
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany.
    Hussain, Saib
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany.
    Walter, Steffi
    Robert Koch Inst, Project Grp 5, D-38855 Wernigerode, Germany.
    Gerlach, Roman G.
    Robert Koch Inst, Project Grp 5, D-38855 Wernigerode, Germany.
    Ruscheweyh, Hans J.
    Univ Tubingen, Ctr Bioinformat, Tubingen, Germany;Swiss Fed Inst Technol, Inst Microbiol, Dept Biol, Zurich, Switzerland.
    Huson, Daniel
    Univ Tubingen, Ctr Bioinformat, Tubingen, Germany.
    Sellin, Mikael E.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Slack, Emma
    Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Inst Food Nutr & Hlth, Zurich, Switzerland.
    Hanson, Buck
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Res Network Chem Meets Microbiol, Althanstr 14, A-1090 Vienna, Austria.
    Loy, Alexander
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Res Network Chem Meets Microbiol, Althanstr 14, A-1090 Vienna, Austria.
    Baines, John F.
    Max Planck Inst Evolutionary Biol, August Thienemann Str 2, D-24306 Plon, Germany.
    Bausch, Philipp
    Univ Copenhagen, Dept Biol, Lab Genom & Mol Biomed, Univ Pk 13, DK-2100 Copenhagen, Denmark.
    Basic, Marijana
    Hannover Med Sch, Inst Lab Anim Sci, D-30625 Hannover, Germany;Hannover Med Sch, Cent Anim Facil, D-30625 Hannover, Germany.
    Bleich, Andre
    Hannover Med Sch, Inst Lab Anim Sci, D-30625 Hannover, Germany;Hannover Med Sch, Cent Anim Facil, D-30625 Hannover, Germany.
    Berry, David
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Res Network Chem Meets Microbiol, Althanstr 14, A-1090 Vienna, Austria.
    Stecher, Baerbel
    Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Pettenkoferstr 9a, D-80336 Munich, Germany;German Ctr Infect Res DZIF, Partner Site LMU Munich, D-80336 Munich, Germany.
    Mucispirillum schaedleri Antagonizes Salmonella Virulence to Protect Mice against Colitis2019Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 25, nr 5, s. 681-694.e8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The microbiota and the gastrointestinal mucus layer play a pivotal role in protection against non-typhoidal Salmonella enterica serovar Typhimurium (S. Tm) colitis. Here, we analyzed the course of Salmonella colitis in mice lacking a functional mucus layer in the gut. Unexpectedly, in contrast to mucus-proficient littermates, genetically deficient mice were protected against Salmonellainduced gut inflammation in the streptomycin colitis model. This correlated with microbiota alterations and enrichment of the bacterial phylum Deferribacteres. Using gnotobiotic mice associated with defined bacterial consortia, we causally linked Mucispirillum schaedleri, currently the sole known representative of Deferribacteres present in the mammalian microbiota, to host protection against S. Tm colitis. Inhibition by M. schaedleri involves interference with S. Tm invasion gene expression, partly by competing for anaerobic electron acceptors. In conclusion, this study establishes M. schaedleri, a core member of the murine gut microbiota, as a key antagonist of S. Tm virulence in the gut.

  • 12. Jin, Jing
    et al.
    Galaz-Montoya, Jesus G.
    Sherman, Michael B.
    Sun, Stella Y.
    Goldsmith, Cynthia S.
    O'Toole, Eileen T.
    Ackerman, Larry
    Carlson, Lars-Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Weaver, Scott C.
    Chiu, Wah
    Simmons, Graham
    Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane2018Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 24, nr 3, s. 417-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neutralizing antibodies (NAbs) are traditionally thought to inhibit virus infection by preventing virion entry into target cells. In addition, antibodies can engage Fc receptors (FcRs) on immune cells to activate antiviral responses. We describe a mechanism by which NAbs inhibit chikungunya virus (CHIKV), the most common alphavirus infecting humans, by preventing virus budding from infected human cells and activating IgG-specific Fc gamma receptors. NAbs bind to CHIKV glycoproteins on the infected cell surface and induce glycoprotein coalescence, preventing budding of nascent virions and leaving structurally heterogeneous nucleocapsids arrested in the cytosol. Furthermore, NAbs induce clustering of CHIKV replication spherules at sites of budding blockage. Functionally, these densely packed glycoprotein-NAb complexes on infected cells activate Fc gamma receptors, inducing a strong, antibody-dependent, cell-mediated cytotoxicity response from immune effector cells. Our findings describe a triply functional antiviral pathway for NAbs that might be broadly applicable across virus-host systems, suggesting avenues for therapeutic innovation through antibody design.

  • 13. Kirienko, Natalia V.
    et al.
    Kirienko, Daniel R.
    Larkins-Ford, Jonah
    Wählby, Carolina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ruvkun, Gary
    Ausubel, Frederick M.
    Pseudomonas aeruginosa Disrupts Caenorhabditis elegans Iron Homeostasis, Causing a Hypoxic Response and Death2013Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 13, nr 4, s. 406-416Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The opportunistic pathogen Pseudomonas aeruginosa causes serious human infections, but effective treatments and the mechanisms mediating pathogenesis remain elusive. Caenorhabditis elegans shares innate immune pathways with humans, making it invaluable to investigate infection. To determine how P. aeruginosa disrupts host biology, we studied how P. aeruginosa kills C. elegans in a liquid-based pathogenesis model. We found that P. aeruginosa-mediated killing does not require quorum-sensing pathways or host colonization. A chemical genetic screen revealed that iron chelators alleviate P. aeruginosa-mediated killing. Consistent with a role for iron in P. aeruginosa pathogenesis, the bacterial siderophore pyoverdin was required for virulence and was sufficient to induce a hypoxic response and death in the absence of bacteria. Loss of the C. elegans hypoxia-inducing factor HIF-1, which regulates iron homeostasis, exacerbated P. aeruginosa pathogenesis, further linking hypoxia and killing. As pyoverdin is indispensable for virulence in mice, pyoverdin-mediated hypoxia is likely to be relevant in human pathogenesis.

  • 14. Konradt, Christoph
    et al.
    Frigimelica, Elisabetta
    Nothelfer, Katharina
    Puhar, Andrea
    Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 25–28 Rue du Dr Roux, 75724 Paris Cedex 15, France, and INSERM U786, Institut Pasteur, 25–28 Rue du Dr Roux, 75724 Paris Cedex 15, France .
    Salgado-Pabon, Wilmara
    di Bartolo, Vincenzo
    Scott-Algara, Daniel
    Rodrigues, Cristina D
    Sansonetti, Philippe J
    Phalipon, Armelle
    The Shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism2011Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 9, nr 4, s. 263-272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Shigella, the Gram-negative enteroinvasive bacterium that causes shigellosis, relies on its type III secretion system (TTSS) and injected effectors to modulate host cell functions. However, consequences of the interaction between Shigella and lymphocytes have not been investigated. We show that Shigella invades activated human CD4(+) T lymphocytes. Invasion requires a functional TTSS and results in inhibition of chemokine-induced T cell migration, an effect mediated by the TTSS effector IpgD, a phosphoinositide 4-phosphatase. Remarkably, IpgD injection into bystander T cells can occur in the absence of cell invasion. Upon IpgD-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP(2)), the pool of PIP(2) at the plasma membrane is reduced, leading to dephosphorylation of the ERM proteins and their inability to relocalize at one T cell pole upon chemokine stimulus, likely affecting the formation of the polarized edge required for cell migration. These results reveal a bacterial TTSS effector-mediated strategy to impair T cell function.

  • 15.
    Kostic, Aleksandar D.
    et al.
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Center for Computational and Integrative Bioogy, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Gevers, Dirk
    Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Siljander, Heli
    Department of Biostatistics, Harvard School of Public Health, Boston MA, United States; Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
    Vatanen, Tommi
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Department of Information and Computer Science, Aalto University School of Science, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Hämäläinen, Anu-Maaria
    Department of Pediatrics, Jorvi Hospital, Espoo, Finland.
    Peet, Aleksandr
    Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, Tartu, Estonia.
    Tillmann, Vallo
    Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, Tartu, Estonia.
    Pöhö, Päivi
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Lähdesmäki, Harri
    Franzosa, Eric A.
    Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Vaarala, Outi
    Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    de Goffau, Marcus
    Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Harmsen, Hermie
    Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Ilonen, Jorma
    Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
    Virtanen, Suvi M.
    Department of Lifestyle and Participation, National Institute for Health and Welfare, Helsinki, Finland; School of Health Sciences, University of Tampere, Tampere, Finland; Science Centre, Pirkanmaa Hospital District, Tampere, Finland.
    Clish, Clary B.
    Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Broad Institute of MIT and Harvard, Cambridge MA, United States; VTT Technical Research Centre of Finland, Espoo, Finland.
    Huttenhower, Curtis
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Knip, Mikael
    Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Xavier, Ramnik J.
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge MA, United States.
    The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes2015Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 17, nr 2, s. 260-273, artikel-id S1931-3128(15)00021-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.

  • 16.
    Lauber, Chris
    et al.
    Tech Univ Dresden, Inst Med Informat & Biometry, D-01307 Dresden, Germany..
    Seitz, Stefan
    Heidelberg Univ, Dept Infect Dis, Mol Virol, D-69120 Heidelberg, Germany..
    Mattei, Simone
    European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany..
    Suh, Alexander
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Beck, Juergen
    Univ Hosp Freiburg, Dept Internal Med Mol Biol 2, D-79106 Freiburg, Germany..
    Herstein, Jennifer
    Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA..
    Boerold, Jacob
    Heidelberg Univ, Dept Infect Dis, Mol Virol, D-69120 Heidelberg, Germany..
    Salzburger, Walter
    Univ Basel, Inst Zool, CH-4051 Basel, Switzerland..
    Kaderali, Lars
    Tech Univ Dresden, Inst Med Informat & Biometry, D-01307 Dresden, Germany.;Univ Med Greifswald, Inst Bioinformat, D-17487 Greifswald, Germany..
    Briggs, John A. G.
    European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany..
    Bartenschlager, Ralf
    Heidelberg Univ, Dept Infect Dis, Mol Virol, D-69120 Heidelberg, Germany.;German Canc Res Ctr, Div Virus Associated Carcinogenesis, D-69120 Heidelberg, Germany..
    Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses2017Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 22, nr 3, s. 387-399,e1-e6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the similar to 1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via proteinprimed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.

  • 17. Meinzer, Ulrich
    et al.
    Barreau, Frederick
    Esmiol-Welterlin, Sophie
    Jung, Camille
    Villard, Claude
    Leger, Thibaut
    Ben-Mkaddem, Sanah
    Berrebi, Dominique
    Dussaillant, Monique
    Alnabhani, Ziad
    Roy, Maryline
    Bonacorsi, Stephane
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Perroy, Julie
    Ollendorff, Vincent
    Hugot, Jean-Pierre
    Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction2012Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 11, nr 4, s. 337-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1 beta. Finally, IL-1 beta within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.

  • 18. Modrzynska, Katarzyna
    et al.
    Pfander, Claudia
    Chappell, Lia
    Yu, Lu
    Suarez, Catherine
    Dundas, Kirsten
    Gomes, Ana Rita
    Goulding, David
    Rayner, Julian C.
    Choudhary, Jyoti
    Billker, Oliver
    Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    A Knockout Screen of ApiAP2 Genes Reveals Networks of Interacting Transcriptional Regulators Controlling the Plasmodium Life Cycle2017Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, nr 1, s. 11-22Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A family of apicomplexa-specific proteins containing AP2 DNA-binding domains (ApiAP2s) was identified in malaria parasites. This family includes sequence-specific transcription factors that are key regulators of development. However, functions for the majority of ApiAP2 genes remain unknown. Here, a systematic knockout screen in Plasmodium berghei identified ten ApiAP2 genes that were essential for mosquito transmission: four were critical for the formation of infectious ookinetes, and three were required for sporogony. We describe non-essential functions for AP2-O and AP2-SP proteins in blood stages, and identify AP2-G2 as a repressor active in both asexual and sexual stages. Comparative transcriptomics across mutants and developmental stages revealed clusters of co-regulated genes with shared cis promoter elements, whose expression can be controlled positively or negatively by different ApiAP2 factors. We propose that stage-specific interactions between ApiAP2 proteins on partly overlapping sets of target genes generate the complex transcriptional network that controls the Plasmodium life cycle.

  • 19. Moonens, Kristof
    et al.
    Gideonsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Subedi, Suresh
    Bugaytsova, Jeanna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Romao, Ema
    Mendez, Melissa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nordén, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Fallah, Mahsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rakhimova, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shevtsova, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lahmann, Martina
    Castaldo, Gaetano
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Coppens, Fanny
    Lo, Alvin W.
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Solnick, Jay V.
    Vandenbussche, Guy
    Oscarson, Stefan
    Hammarström, Lennart
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berg, Douglas E.
    Muyldermans, Serge
    Borén, Thomas
    Remaut, Han
    Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori2016Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, nr 1, s. 55-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

  • 20. Pino, Paco
    et al.
    Sebastian, Sarah
    Kim, Eunbin Arin
    Bush, Erin
    Brochet, Mathieu
    Volkmann, Katrin
    Kozlowski, Elyse
    Llinás, Manuel
    Billker, Oliver
    Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    Soldati-Favre, Dominique
    A tetracycline-repressible transactivator system to study essential genes in malaria parasites2012Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 12, nr 6, s. 824-834Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A major obstacle in analyzing gene function in apicomplexan parasites is the absence of a practical regulatable expression system. Here, we identified functional transcriptional activation domains within Apicomplexan AP2 (ApiAP2) family transcription factors. These ApiAP2 transactivation domains were validated in blood-, liver-, and mosquito-stage parasites and used to create a robust conditional expression system for stage-specific, tetracycline-dependent gene regulation in Toxoplasma gondii, Plasmodium berghei, and Plasmodium falciparum. To demonstrate the utility of this system, we created conditional knockdowns of two essential P. berghei genes: profilin (PRF), a protein implicated in parasite invasion, and N-myristoyltransferase (NMT), which catalyzes protein acylation. Tetracycline-induced repression of PRF and NMT expression resulted in a dramatic reduction in parasite viability. This efficient regulatable system will allow for the functional characterization of essential proteins that are found in these important parasites.

  • 21. Sangaré, Lamba Omar
    et al.
    Ólafsson, Einar B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wang, Yifan
    Yang, Ninghan
    Julien, Lindsay
    Camejo, Ana
    Pesavento, Patricia
    Sidik, Saima M.
    Lourido, Sebastian
    Barragan, Antonio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Saeij, Jeroen P. J.
    In Vivo CRISPR Screen Identifies TgWIP as a Toxoplasma Modulator of Dendritic Cell Migration2019Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 26, nr 4, s. 478-492Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Toxoplasma can reach distant organs, especially the brain, leading to a lifelong chronic phase. However, genes involved in related in vivo processes are currently unknown. Here, we use focused CRISPR libraries to identify Toxoplasma genes that affect in vivo fitness. We focus on TgWIP, whose deletion affects Toxoplasmadissemination to distant organs. We show that TgWIP is secreted into the host cell upon invasion and interacts with the host WAVE regulatory complex and SHP2 phosphatase, both of which regulate actin dynamics. TgWIP affects the morphology of dendritic cells and mediates the dissolution of podosomes, which dendritic cells use to adhere to extracellular matrix. TgWIP enhances the motility and transmigration of parasitized dendritic cells, likely explaining its effect on in vivofitness. Our results provide a framework for systemic identification of Toxoplasmagenes with in vivo effects at the site of infection or on dissemination to distant organs, including the brain.

  • 22.
    Schröder, Björn
    et al.
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Birchenough, George M H
    Ståhlman, Marcus
    Arike, Liisa
    Johansson, Malin E V
    Hansson, Gunnar C
    Bäckhed, Fredrik
    Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration2018Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 23, nr 1, s. 27-40.e7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diet strongly affects gut microbiota composition, and gut bacteria can influence the colonic mucus layer, a physical barrier that separates trillions of gut bacteria from the host. However, the interplay between a Western style diet (WSD), gut microbiota composition, and the intestinal mucus layer is less clear. Here we show that mice fed a WSD have an altered colonic microbiota composition that causes increased penetrability and a reduced growth rate of the inner mucus layer. Both barrier defects can be prevented by transplanting microbiota from chow-fed mice. In addition, we found that administration of Bifidobacterium longum was sufficient to restore mucus growth, whereas administration of the fiber inulin prevented increased mucus penetrability in WSD-fed mice. We hypothesize that the presence of distinct bacteria is crucial for proper mucus function. If confirmed in humans, these findings may help to better understand diseases with an affected mucus layer, such as ulcerative colitis.

  • 23. Sebastian, Sarah
    et al.
    Brochet, Mathieu
    Collins, Mark O.
    Schwach, Frank
    Jones, Matthew L.
    Goulding, David
    Rayner, Julian C.
    Choudhary, Jyoti S.
    Billker, Oliver
    Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs2012Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 12, nr 1, s. 9-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Calcium-dependent protein kinases (CDPKs) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. Using the rodent malaria parasite Plasmodium berghei, we show that CDPK1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. Knockdown of CDPK1 in sexual stages resulted in developmentally arrested parasites and prevented mosquito transmission, and these effects were independent of the previously proposed function for CDPK1 in regulating parasite motility. In-depth translational and transcriptional profiling of arrested parasites revealed that CDPK1 translationally activates mRNA species in the developing zygote that in macrogametes remain repressed via their 3' and 5'UTRs. These findings indicate that CDPK1 is a multifunctional protein that translationally regulates mRNAs to ensure timely and stage-specific protein expression.

  • 24.
    Sellin, Mikael E.
    et al.
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Müller, Anna A.
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Felmy, Boas
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Dolowschiak, Tamas
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Diard, Médéric
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Tardivel, Aubry
    Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
    Maslowski, Kendle M.
    Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Japan.
    Wolf-Dietrich, Hardt
    Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
    Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa2014Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 16, nr 2, s. 237-248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.

  • 25. Tewari, Rita
    et al.
    Straschil, Ursula
    Bateman, Alex
    Böhme, Ulrike
    Cherevach, Inna
    Gong, Peng
    Pain, Arnab
    Billker, Oliver
    Division of Cell & Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK; The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission2010Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 8, nr 4, s. 377-387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although eukaryotic protein kinases (ePKs) contribute to many cellular processes, only three Plasmodium falciparum ePKs have thus far been identified as essential for parasite asexual blood stage development. To identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of ePKs in the genetically tractable rodent parasite Plasmodium berghei. Modeling domain signatures of conventional ePKs identified 66 putative Plasmodium ePKs. Kinomes are highly conserved between Plasmodium species. Using reverse genetics, we show that 23 ePKs are redundant for asexual erythrocytic parasite development in mice. Phenotyping mutants at four life cycle stages in Anopheles stephensi mosquitoes revealed functional clusters of kinases required for sexual development and sporogony. Roles for a putative SR protein kinase (SRPK) in microgamete formation, a conserved regulator of clathrin uncoating (GAK) in ookinete formation, and a likely regulator of energy metabolism (SNF1/KIN) in sporozoite development were identified.

  • 26. Zhang, Sicai
    et al.
    Lebreton, Francois
    Mansfield, Michael J.
    Miyashita, Shin-Ichiro
    Zhang, Jie
    Schwartzman, Julia A.
    Tao, Liang
    Masuyer, Geoffrey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Martínez-Carranza, Markel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Stenmark, Pål
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gilmore, Michael S.
    Doxey, Andrew C.
    Dong, Min
    Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium2018Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 23, nr 2, s. 169-176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Botulinumneurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT-like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster.

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