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  • 1.
    Bastidas, Robert J.
    et al.
    Department of Integrative Immunobiology, Duke University, Durham, United States.
    Kędzior, Mateusz
    Department of Integrative Immunobiology, Duke University, Durham, United States.
    Davidson, Robert K.
    Department of Molecular Genetics and Microbiology, Duke University, Duke, United States.
    Walsh, Stephen C.
    Department of Molecular Genetics and Microbiology, Duke University, Duke, United States.
    Dolat, Lee
    Department of Integrative Immunobiology, Duke University, Durham, United States.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pruneda, Jonathan N.
    Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, United States.
    Coers, Jörn
    Department of Integrative Immunobiology, Duke University, Durham, United States; Department of Molecular Genetics and Microbiology, Duke University, Duke, United States.
    Valdivia, Raphael H.
    Department of Integrative Immunobiology, Duke University, Durham, United States; Department of Molecular Genetics and Microbiology, Duke University, Duke, United States.
    The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protecting Chlamydia effectors from degradation2024In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id 87386Article in journal (Refereed)
    Abstract [en]

    Many cellular processes are regulated by ubiquitin-mediated proteasomal degradation. Pathogens can regulate eukaryotic proteolysis through the delivery of proteins with de-ubiquitinating (DUB) activities. The obligate intracellular pathogen Chlamydia trachomatis secretes Cdu1 (ChlaDUB1), a dual deubiquitinase and Lys-acetyltransferase, that promotes Golgi remodeling and survival of infected host cells presumably by regulating the ubiquitination of host and bacterial proteins. Here, we determined that Cdu1's acetylase but not its DUB activity is important to protect Cdu1 from ubiquitin-mediated degradation. We further identified three C. trachomatis proteins on the pathogen-containing vacuole (InaC, IpaM, and CTL0480) that required Cdu1's acetylase activity for protection from degradation and determined that Cdu1 and these Cdu1-protected proteins are required for optimal egress of Chlamydia from host cells. These findings highlight a non-canonical mechanism of pathogen-mediated protection of virulence factors from degradation after their delivery into host cells and the coordinated regulation of secreted effector proteins.

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  • 2.
    Filcek, Kimberly
    et al.
    University of Maryland, Department of Microbial Pathogenesis.
    Vielfort, Katarina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Muraleedharan, Samada
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael
    Duke University, Department of Molecular Genetics and Microbiology.
    Bavoil, Patrik
    University of Maryland, Department of Microbial Pathogenesis.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America.
    Insertional mutagenesis in the zoonotic pathogen Chlamydia caviae2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 11, article id e0224324Article in journal (Refereed)
    Abstract [en]

    The ability to introduce targeted genetic modifications in microbial genomes has revolutionized our ability to study the role and mode of action of individual bacterial virulence factors. Although the fastidious lifestyle of obligate intracellular bacterial pathogens poses a technical challenge to such manipulations, the last decade has produced significant advances in our ability to conduct molecular genetic analysis in Chlamydia trachomatis, a major bacterial agent of infertility and blindness. Similar approaches have not been established for the closely related veterinary Chlamydia spp., which cause significant economic damage, as well as rare but potentially life-threatening infections in humans. Here we demonstrate the feasibility of conducting site-specific mutagenesis for disrupting virulence genes in Ccaviae, an agent of guinea pig inclusion conjunctivitis that was recently identified as a zoonotic agent in cases of severe community-acquired pneumonia. Using this approach, we generated Ccaviae mutants deficient for the secreted effector proteins IncA and SinC. We demonstrate that Ccaviae IncA plays a role in mediating fusion of the bacteria-containing vacuoles inhabited by Ccaviae. Moreover, using a chicken embryo infection model, we provide first evidence for a role of SinC in Ccaviae virulence in vivo.

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  • 3.
    Fluckiger, Aurélie
    et al.
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Daillere, Romain
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; everImmune, Gustave Roussy Cancer Center, Villejuif, France.
    Sassi, Mohamed
    Université Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Liu, Peng
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Loos, Friedemann
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Richard, Corentin
    Research Platform in Biological Oncology, Dijon, France; GIMI Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy-Franche Comté, Dijon, France.
    Rabu, Catherine
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Alou, Maryam Tidjani
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Goubet, Anne-Gaelle
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Lemaitre, Fabien
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; everImmune, Gustave Roussy Cancer Center, Villejuif, France.
    Ferrere, Gladys
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Derosa, Lisa
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Université Paris-Saclay, Villejuif, F-94805, France.
    Duong, Connie P. M.
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Messaoudene, Meriem
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    Gagne, Andreanne
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    Joubert, Philippe
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    De Sordi, Luisa
    Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France; Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS_938, Paris, France.
    Debarbieux, Laurent
    Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France.
    Simon, Sylvain
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Scarlata, Clara-Maria
    Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France.
    Ayyoub, Maha
    Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France.
    Palermo, Belinda
    Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Facciolo, Francesco
    Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Boidot, Romain
    Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Anticancer Center, UNICANCER, Dijon, France.
    Wheeler, Richard
    Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France.
    Boneca, Ivo Gomperts
    Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France.
    Sztupinszki, Zsofia
    Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA.
    Papp, Krisztian
    Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.
    Csabai, Istvan
    Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.
    Pasolli, Edoardo
    Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy.
    Segata, Nicola
    Department CIBIO, University of Trento, Trento, Italy.
    Lopez-Otin, Carlos
    Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France; Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
    Szallasi, Zoltan
    Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA; Danish Cancer Society Research Center, Copenhagen, Denmark; MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
    Andre, Fabrice
    Department of Cancer Medicine, Breast Cancer Committee, Gustave Roussy, Villejuif, France; INSERM Unit 981, Gustave Roussy, Villejuif, France.
    Iebba, Valerio
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Department of Medical Sciences, University of Trieste, 34137 Trieste, Italy.
    Quiniou, Valentin
    AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France; Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France.
    Klatzmann, David
    AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France; Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France.
    Boukhalil, Jacques
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Khelaifia, Saber
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Raoult, Didier
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Albiges, Laurence
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France.
    Escudier, Bernard
    ustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; INSERM U981, GRCC, Villejuif, France.
    Eggermont, Alexander
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Princess Maxima Center, CS 3584 Utrecht, the Netherlands.
    Mami-Chouaib, Fathia
    INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Fac. de Médecine - Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
    Nistico, Paola
    Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy; Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Ghiringhelli, Francois
    Department of Medical Oncology, Center GF Leclerc, Dijon, France.
    Routy, Bertrand
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada; Division d'Hémato-Oncologie, Département de Médicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
    Labarriere, Nathalie
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Cattoir, Vincent
    Université Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France; CHU de Rennes - Hôpital Ponchaillou, Service de Bactériologie-Hygiène Hospitalière, Rennes, France; CNR de la Résistance aux Antibiotiques (laboratoire associé 'Entérocoques'), Rennes, France..
    Kroemer, Guido
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France. Sorbonne Université, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China; Institut Universitaire de France, Paris, France.
    Zitvogel, Laurence
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Université Paris-Saclay, Villejuif, F-94805, France; Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China.
    Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage2020In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 369, no 6506, p. 936-942Article in journal (Refereed)
    Abstract [en]

    Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.

  • 4.
    Halter, Tamara
    et al.
    Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria; Doctoral School in Microbiology and Environmental Science, University of Vienna, Vienna, Austria.
    Köstlbacher, Stephan
    Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria; Doctoral School in Microbiology and Environmental Science, University of Vienna, Vienna, Austria.
    Collingro, Astrid
    Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Tönshoff, Elena R.
    Institute of Molecular Biology and Biophysics, Eidgenössische Technische Hochschule Zürich (ETH), Zurich, Switzerland.
    Hendrickx, Frederik
    Royal Belgian Institute of Natural Sciences, Brussels, Belgium.
    Kostanjšek, Rok
    Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
    Horn, Matthias
    Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.
    Ecology and evolution of chlamydial symbionts of arthropods2022In: ISME Communications, E-ISSN 2730-6151, Vol. 2, no 1, article id 45Article in journal (Refereed)
    Abstract [en]

    The phylum Chlamydiae consists of obligate intracellular bacteria including major human pathogens and diverse environmental representatives. Here we investigated the Rhabdochlamydiaceae, which is predicted to be the largest and most diverse chlamydial family, with the few described members known to infect arthropod hosts. Using published 16 S rRNA gene sequence data we identified at least 388 genus-level lineages containing about 14 051 putative species within this family. We show that rhabdochlamydiae are mainly found in freshwater and soil environments, suggesting the existence of diverse, yet unknown hosts. Next, we used a comprehensive genome dataset including metagenome assembled genomes classified as members of the family Rhabdochlamydiaceae, and we added novel complete genome sequences of Rhabdochlamydia porcellionis infecting the woodlouse Porcellio scaber, and of 'Candidatus R. oedothoracis' associated with the linyphiid dwarf spider Oedothorax gibbosus. Comparative analysis of basic genome features and gene content with reference genomes of well-studied chlamydial families with known host ranges, namely Parachlamydiaceae (protist hosts) and Chlamydiaceae (human and other vertebrate hosts) suggested distinct niches for members of the Rhabdochlamydiaceae. We propose that members of the family represent intermediate stages of adaptation of chlamydiae from protists to vertebrate hosts. Within the genus Rhabdochlamydia, pronounced genome size reduction could be observed (1.49-1.93 Mb). The abundance and genomic distribution of transposases suggests transposable element expansion and subsequent gene inactivation as a mechanism of genome streamlining during adaptation to new hosts. This type of genome reduction has never been described before for any member of the phylum Chlamydiae. This study provides new insights into the molecular ecology, genomic diversity, and evolution of representatives of one of the most divergent chlamydial families.

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  • 5. Leitsch, David
    et al.
    Köhsler, Martina
    Marchetti-Deschmann, Martina
    Deutsch, Andrea
    Allmaier, Günter
    König, Lena
    Sixt, Barbara S.
    Department of Microbial Ecology, University of Vienna, Vienna, Austria.
    Duchêne, Michael
    Walochnik, Julia
    Proteomic aspects of Parachlamydia acanthamoebae infection in Acanthamoeba spp.2010In: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 4, no 11, p. 1366-1374Article in journal (Refereed)
    Abstract [en]

    The free-living but facultatively pathogenic amoebae of the genus Acanthamoeba are frequently infected with bacterial endosymbionts that can have a profound influence on the physiology and viability of their host. Parachlamydia acanthamoebae, a chlamydial endosymbiont in acanthamoebae, is known to be either symbiotic or lytic to its host, depending on the ambient conditions, for example, temperature. Moreover, parachlamydiae can also inhibit the encystment process in Acanthamoeba, an essential survival strategy of their host for the evasion of chemotherapeutic agents, heat, desiccation and radiation. To obtain a more detailed picture of the intracellular interactions of parachlamydiae and acanthamoebae, we studied parachlamydial infection in several Acanthamoeba isolates at the proteomic level by means of two-dimensional gel electrophoresis (2DE) and mass spectrometry. We observed that P. acanthamoebae can infect all three morphological subtypes of the genus Acanthamoeba and that the proteome pattern of released P. acanthamoebae elementary bodies was always practically identical regardless of the Acanthamoeba strain infected. Moreover, by comparing proteome patterns of encysting cells from infected and uninfected Acanthamoeba cultures, it was shown that encystment is blocked by P. acanthamoebae at a very early stage. Finally, on 2D-gels of purified P. acanthamoebae from culture supernatants, a subunit of the NADH-ubiquinone oxidoreductase complex, that is, an enzyme that has been described as an indicator for bacterial virulence was identified by a mass spectrometric and bioinformatic approach.

  • 6.
    Meier, Karsten
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Jachmann, Lana H.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Türköz, Gözde
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Babu Sait, Mohammed Rizwan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pérez, Lucía
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kepp, Oliver
    Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
    Valdivia, Raphael H.
    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, NC, Durham, United States.
    Kroemer, Guido
    Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Department of Biology, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab352023In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 4, article id e0319022Article in journal (Refereed)
    Abstract [en]

    The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy.

    IMPORTANCE: Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.

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  • 7. Omsland, Anders
    et al.
    Sixt, Barbara Susanne
    Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, University of Vienna, Vienna, Austria.
    Horn, Matthias
    Hackstadt, Ted
    Chlamydial metabolism revisited: interspecies metabolic variability and developmental stage-specific physiologic activities2014In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 38, no 4, p. 779-801Article in journal (Refereed)
    Abstract [en]

    Chlamydiae are a group of obligate intracellular bacteria comprising important human and animal pathogens as well as symbionts of ubiquitous protists. They are characterized by a developmental cycle including two main morphologically and physiologically distinct stages, the replicating reticulate body and the infectious nondividing elementary body. In this review, we reconstruct the history of studies that have led to our current perception of chlamydial physiology, focusing on their energy and central carbon metabolism. We then compare the metabolic capabilities of pathogenic and environmental chlamydiae highlighting interspecies variability among the metabolically more flexible environmental strains. We discuss recent findings suggesting that chlamydiae may not live as energy parasites throughout the developmental cycle and that elementary bodies are not metabolically inert but exhibit metabolic activity under appropriate axenic conditions. The observed host-free metabolic activity of elementary bodies may reflect adequate recapitulation of the intracellular environment, but there is evidence that this activity is biologically relevant and required for extracellular survival and maintenance of infectivity. The recent discoveries call for a reconsideration of chlamydial metabolism and future in-depth analyses to better understand how species- and stage-specific differences in chlamydial physiology may affect virulence, tissue tropism, and host adaptation.

  • 8. Schott, Benjamin H.
    et al.
    Antonia, Alejandro L.
    Wang, Liuyang
    Pittman, Kelly J.
    Sixt, Barbara Susanne
    Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, USA.
    Barnes, Alyson B.
    Valdivia, Raphael H.
    Ko, Dennis C.
    Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18269Article in journal (Refereed)
    Abstract [en]

    Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by both host genetic diversity and pathogen immune evasion. Previously, we discovered a single nucleotide polymorphism (rs2869462) associated with absolute abundance of CXCL10, a pro-inflammatory T-cell chemokine. Here, we report that levels of CXCL10 change during C. trachomatis infection of cultured cells in a manner dependent on both host and pathogen. Linear modeling of cellular traits associated with CXCL10 levels identified a strong, negative correlation with bacterial burden, suggesting that C. trachomatis actively suppresses CXCL10. We identified the pathogen-encoded factor responsible for this suppression as the chlamydial protease- or proteasome-like activity factor, CPAF. Further, we applied our modeling approach to other host cytokines in response to C. trachomatis and found evidence that RANTES, another T-cell chemoattractant, is actively suppressed by Chlamydia. However, this observed suppression of RANTES is not mediated by CPAF. Overall, our results demonstrate that CPAF suppresses CXCL10 to evade the host cytokine response and that modeling of cellular infection parameters can reveal previously unrecognized facets of host-pathogen interactions.

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  • 9.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Host cell death during infection with Chlamydia: a double-edged sword2021In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 45, no 1, article id fuaa043Article in journal (Refereed)
    Abstract [en]

    The phylum Chlamydiae constitutes a group of obligate intracellular bacteria that infect a remarkably diverse range of host species. Some representatives are significant pathogens of clinical or veterinary importance. For instance, Chlamydia trachomatis is the leading infectious cause of blindness and the most common bacterial agent of sexually transmitted diseases. Chlamydiae are exceptionally dependent on their eukaryotic host cells as a consequence of their developmental biology. At the same time, host cell death is an integral part of the chlamydial infection cycle. It is therefore not surprising that the bacteria have evolved exquisite and versatile strategies to modulate host cell survival and death programs to their advantage. The recent introduction of tools for genetic modification of Chlamydia spp., in combination with our increasing awareness of the complexity of regulated cell death in eukaryotic cells, and in particular of its connections to cell-intrinsic immunity, has revived the interest in this virulence trait. However, recent advances also challenged long-standing assumptions and highlighted major knowledge gaps. This review summarizes current knowledge in the field and discusses possible directions for future research, which could lead us to a deeper understanding of Chlamydia's virulence strategies and may even inspire novel therapeutic approaches.

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  • 10.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Keeping the home intact—lessons from Chlamydia2022In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 30, no 4, p. 475-479Article in journal (Other academic)
    Abstract [en]

    5 years ago, my colleagues and I revealed the Chlamydia trachomatis virulence factor CpoS as a suppressor of host cell-autonomous immunity. Here, I reflect on the events that inspired and enabled this research and place our discoveries in context to past and most recent discoveries in the field.

  • 11.
    Sixt, Barbara Susanne
    et al.
    Department of Molecular Genetics and Microbiology, Duke University, Durham, USA; INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
    Bastidas, Robert J.
    Finethy, Ryan
    Baxter, Ryan M.
    Carpenter, Victoria K.
    Kroemer, Guido
    Coers, Jörn
    Valdivia, Raphael H.
    The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs2017In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 1, p. 113-121Article in journal (Refereed)
    Abstract [en]

    Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway. Disruption of STING, but not cGAS or IRF3, attenuated cell death, suggesting that STING mediates Chlamydia-induced cell death independent of its role in regulating interferon responses. CpoS-deficient strains are attenuated in their ability to propagate in cell culture and are cleared faster from the murine genital tract, highlighting the importance of CpoS for Chlamydia pathogenesis.

  • 12.
    Sixt, Barbara Susanne
    et al.
    Department of Microbial Ecology, University of Vienna, Vienna, Austria.
    Heinz, Christian
    Pichler, Peter
    Heinz, Eva
    Montanaro, Jacqueline
    Op den Camp, Huub J.M.
    Ammerer, Gustav
    Mechtler, Karl
    Wagner, Michael
    Horn, Matthias
    Proteomic analysis reveals a virtually complete set of proteins for translation and energy generation in elementary bodies of the amoeba symbiont Protochlamydia amoebophila2011In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 11, no 10, p. 1868-1892Article in journal (Refereed)
    Abstract [en]

    Chlamydiae belong to the most successful intracellular bacterial pathogens. They display a complex developmental cycle and an extremely broad host spectrum ranging from vertebrates to protozoa. The family Chlamydiaceae comprises exclusively well-known pathogens of humans and animals, whereas the members of its sister group, the Parachlamydiaceae, naturally occur as symbionts of free-living amoebae. Comparative analysis of these two groups provides valuable insights into chlamydial evolution and mechanisms for microbe-host interaction. Based on the complete genome sequence of the Acanthamoeba spp. symbiont Protochlamydia amoebophila UWE25, we performed the first detailed proteome analysis of the infectious stage of a symbiotic chlamydia. A 2-D reference proteome map was established and the analysis was extensively complemented by shotgun proteomics. In total, 472 proteins were identified, which represent 23.2% of all encoded proteins. These cover a wide range of functional categories, including typical house-keeping proteins, but also putative virulence-associated proteins. A number of proteins that are not encoded in genomes of Chlamydiaceae were observed and the expression of 162 proteins classified as hypothetical or unknown proteins could be demonstrated. Our findings indicate that P. amoebophila exploits its additional genetic repertoire (compared with the Chlamydiaceae), and that its elementary bodies are remarkably well equipped with proteins involved in transcription, translation, and energy generation.

  • 13.
    Sixt, Barbara Susanne
    et al.
    Department of Microbial Ecology, University of Vienna, Vienna, Austria.
    Hiess, Birgit
    König, Lena
    Horn, Matthias
    Lack of effective anti-apoptotic activities restricts growth of Parachlamydiaceae in insect cells2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 1, article id e29565Article in journal (Refereed)
    Abstract [en]

    The fundamental role of programmed cell death in host defense is highlighted by the multitude of anti-apoptotic strategies evolved by various microbes, including the well-known obligate intracellular bacterial pathogens Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. As inhibition of apoptosis is assumed to be essential for a successful infection of humans by these chlamydiae, we analyzed the anti-apoptotic capacity of close relatives that occur as symbionts of amoebae and might represent emerging pathogens. While Simkania negevensis was able to efficiently replicate within insect cells, which served as model for metazoan-derived host cells, the Parachlamydiaceae (Parachlamydia acanthamoebae and Protochlamydia amoebophila) displayed limited intracellular growth, yet these bacteria induced typical features of apoptotic cell death, including formation of apoptotic bodies, nuclear condensation, internucleosomal DNA fragmentation, and effector caspase activity. Induction of apoptosis was dependent on bacterial activity, but not bacterial de novo protein synthesis, and was detectable already at very early stages of infection. Experimental inhibition of host cell death greatly enhanced parachlamydial replication, suggesting that lack of potent anti-apoptotic activities in Parachlamydiaceae may represent an important factor compromising their ability to successfully infect non-protozoan hosts. These findings highlight the importance of the evolution of anti-apoptotic traits for the success of chlamydiae as pathogens of humans and animals.

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  • 14.
    Sixt, Barbara Susanne
    et al.
    Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria.
    Kostanjšek, Rok
    Mustedanagic, Azra
    Toenshoff, Elena R.
    Horn, Matthias
    Developmental cycle and host interaction of Rhabdochlamydia porcellionis, an intracellular parasite of terrestrial isopods2013In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 15, no 11, p. 2980-2993Article in journal (Refereed)
    Abstract [en]

    Environmental chlamydiae are a diverse group of obligate intracellular bacteria related to well-known pathogens of humans. To date, only very little is known about chlamydial species infecting arthropods. In this study, we used cocultivation with insect cells for recovery and maintenance of Rhabdochlamydia porcellionis, a parasite of the crustacean host Porcellio scaber. In vitro, the infection cycle of R. porcellionis was completed within 7 days, resulting in the release of infectious particles by host cell lysis. Lack of apoptosis induction during the entire course of infection, combined with a reduced sensitivity of infected cultures to experimentally induced programmed cell death, indicates that R. porcellionis like its human pathogenic relatives counteracts this host defence mechanism. Interestingly, the rod-shaped variant of R. porcellionis, proposed to represent their mature infective stage, was not detected in cell culture, suggesting that its development may require prolonged maturation or may be triggered by specific conditions encountered only in the animal host. This first cell culture-based system for the cultivation and investigation of an arthropod-associated chlamydial species will help to better understand the biology of a so far neglected group of chlamydiae and its recently suggested potential to cause disease in humans.

  • 15.
    Sixt, Barbara Susanne
    et al.
    INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
    Kroemer, Guido
    [Commentary] Chlamydia Anti-apoptosis - A By-product of Metabolic Reprogramming?2017In: EBioMedicine, E-ISSN 2352-3964, Vol. 23, p. 2-3Article in journal (Refereed)
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  • 16.
    Sixt, Barbara Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
    Núñez-Otero, Carlos
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kepp, Oliver
    INSERM U1138, Centre de Recherche des Cordeliers; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Université Paris Descartes; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy.
    Valdivia, Raphael H
    Duke University School of Medicine, Department of Molecular Genetics and Microbiology.
    Kroemer, Guido
    INSERM U1138, Centre de Recherche des Cordeliers; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Université Paris Descartes; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy.
    Chlamydia trachomatis fails to protect its growth niche against pro-apoptotic insults2019In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 26, no 8, p. 1485-1500Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis is an obligate intracellular bacterial agent responsible for ocular infections and sexually transmitted diseases. It has been postulated that Chlamydia inhibits apoptosis in host cells to maintain an intact replicative niche until sufficient infectious progeny can be generated. Here we report that, while cells infected with C. trachomatis are protected from apoptosis at early and mid-stages of infection, they remain susceptible to the induction of other cell death modalities. By monitoring the fate of infected cells by time-lapse video microscopy and by analyzing host plasma membrane integrity and the activity of caspases, we determined that C. trachomatis-infected cells exposed to pro-apoptotic stimuli predominately died by a mechanism resembling necrosis. This necrotic death of infected cells occurred with kinetics similar to the induction of apoptosis in uninfected cells, indicating that C. trachomatis fails to considerably prolong the lifespan of its host cell when exposed to pro-apoptotic insults. Inhibitors of bacterial protein synthesis partially blocked necrotic death of infected cells, suggesting that the switch from apoptosis to necrosis relies on an active contribution of the bacteria. Tumor necrosis factor alpha (TNF-α)-mediated induction of necrosis in cells infected with C. trachomatis was not dependent on canonical regulators of necroptosis, such as RIPK1, RIPK3, or MLKL, yet was blocked by inhibition or depletion of CASP8. These results suggest that alternative signaling pathways regulate necrotic death in the context of C. trachomatis infections. Finally, consistent with the inability of C. trachomatis to preserve host cell viability, necrosis resulting from pro-apoptotic conditions significantly impaired production of infectious progeny. Taken together, our findings suggest that Chlamydia's anti-apoptotic activities are not sufficient to protect the pathogen's replicative niche.

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  • 17.
    Sixt, Barbara Susanne
    et al.
    Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, University of Vienna, Vienna, Austria.
    Siegl, Alexander
    Müller, Constanze
    Watzka, Margarete
    Wultsch, Anna
    Tziotis, Dimitrios
    Montanaro, Jacqueline
    Richter, Andreas
    Schmitt-Kopplin, Philippe
    Horn, Matthias
    Metabolic features of Protochlamydia amoebophila elementary bodies--a link between activity and infectivity in Chlamydiae2013In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 9, no 8, article id e1003553Article in journal (Refereed)
    Abstract [en]

    The Chlamydiae are a highly successful group of obligate intracellular bacteria, whose members are remarkably diverse, ranging from major pathogens of humans and animals to symbionts of ubiquitous protozoa. While their infective developmental stage, the elementary body (EB), has long been accepted to be completely metabolically inert, it has recently been shown to sustain some activities, including uptake of amino acids and protein biosynthesis. In the current study, we performed an in-depth characterization of the metabolic capabilities of EBs of the amoeba symbiont Protochlamydia amoebophila. A combined metabolomics approach, including fluorescence microscopy-based assays, isotope-ratio mass spectrometry (IRMS), ion cyclotron resonance Fourier transform mass spectrometry (ICR/FT-MS), and ultra-performance liquid chromatography mass spectrometry (UPLC-MS) was conducted, with a particular focus on the central carbon metabolism. In addition, the effect of nutrient deprivation on chlamydial infectivity was analyzed. Our investigations revealed that host-free P. amoebophila EBs maintain respiratory activity and metabolize D-glucose, including substrate uptake as well as host-free synthesis of labeled metabolites and release of labeled CO2 from (13)C-labeled D-glucose. The pentose phosphate pathway was identified as major route of D-glucose catabolism and host-independent activity of the tricarboxylic acid (TCA) cycle was observed. Our data strongly suggest anabolic reactions in P. amoebophila EBs and demonstrate that under the applied conditions D-glucose availability is essential to sustain metabolic activity. Replacement of this substrate by L-glucose, a non-metabolizable sugar, led to a rapid decline in the number of infectious particles. Likewise, infectivity of Chlamydia trachomatis, a major human pathogen, also declined more rapidly in the absence of nutrients. Collectively, these findings demonstrate that D-glucose is utilized by P. amoebophila EBs and provide evidence that metabolic activity in the extracellular stage of chlamydiae is of major biological relevance as it is a critical factor affecting maintenance of infectivity.

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  • 18.
    Sixt, Barbara Susanne
    et al.
    Department for Molecular Genetics and Microbiology, Duke University, Durham, North Carolina; Centre de Recherche des Cordeliers, INSERM U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Université Pierre et Marie Curie, Paris,, France.
    Valdivia, Raphael H.
    Molecular Genetic Analysis of Chlamydia Species2016In: Annual Review of Microbiology, ISSN 0066-4227, E-ISSN 1545-3251, Vol. 70, p. 179-198Article in journal (Refereed)
    Abstract [en]

    Species of Chlamydia are the etiologic agent of endemic blinding trachoma, the leading cause of bacterial sexually transmitted diseases, significant respiratory pathogens, and a zoonotic threat. Their dependence on an intracellular growth niche and their peculiar developmental cycle are major challenges to elucidating their biology and virulence traits. The last decade has seen tremendous advances in our ability to perform a molecular genetic analysis of Chlamydia species. Major achievements include the generation of large collections of mutant strains, now available for forward- and reverse-genetic applications, and the introduction of a system for plasmid-based transformation enabling complementation of mutations; expression of foreign, modified, or reporter genes; and even targeted gene disruptions. This review summarizes the current status of the molecular genetic toolbox for Chlamydia species and highlights new insights into their biology and new challenges in the nascent field of Chlamydia genetics.

  • 19.
    Sixt, Barbara Susanne
    et al.
    INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
    Valdivia, Raphael H.
    Kroemer, Guido
    Chlamydia trachomatis' struggle to keep its host alive2017In: Microbial cell (Graz, Austria), ISSN 2311-2638, Vol. 4, no 3, p. 101-104Article in journal (Refereed)
    Abstract [en]

    Bacteria of the phylum Chlamydiae infect a diverse range of eukaryotic host species, including vertebrate animals, invertebrates, and even protozoa. Characteristics shared by all Chlamydiae include their obligate intracellular lifestyle and a biphasic developmental cycle. The infectious form, the elementary body (EB), invades a host cell and differentiates into the replicative form, the reticulate body (RB), which proliferates within a membrane-bound compartment, the inclusion. After several rounds of division, RBs retro-differentiate into EBs that are then released to infect neighboring cells. The consequence of this obligatory transition between replicative and infectious forms inside cells is that Chlamydiae absolutely depend on the viability and functionality of their host cell throughout the entire infection cycle. We recently conducted a forward genetic screen in Chlamydia trachomatis, a common sexually transmitted human pathogen, and identified a mutant that caused premature death in the majority of infected host cells. We employed emerging genetic tools in Chlamydia to link this cytotoxicity to the loss of the protein CpoS (Chlamydia promoter of survival) that normally localizes to the membrane of the pathogen-containing vacuole. CpoS-deficient bacteria also induced an exaggerated type-1 interferon response in infected cells, produced reduced numbers of infectious EBs in cell culture, and were cleared faster from the mouse genital tract in a transcervical infection model in vivo. The analysis of this CpoS-deficient mutant yielded unique insights into the nature of cell-autonomous defense responses against Chlamydia and highlighted the importance of Chlamydia-mediated control of host cell fate for the success of the pathogen.

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  • 20.
    Ölander, Magnus
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sixt, Barbara S.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bringing genetics to heretofore intractable obligate intracellular bacterial pathogens: Chlamydia and beyond2022In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 18, no 7, article id e1010669Article in journal (Refereed)
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