Our team is interested in understanding and analyzing the interactions of pathogens with their host, leading to its infection and possible destruction. Our targets of interest are diverse and include (i) bacteriophages, (ii) type 6 and type 9 secretion systems, and (iii) the host immune response with a particular focus on the role of antibodies.

Understanding host-pathogen interactions is at the heart of the fight against pathogens involved in infectious diseases (viruses, bacteria).

For about ten years, we have been studying the structure and adhesion mechanism of bacteriophages (viruses infecting bacteria) infecting the bacterium used in the milk industry, Lactococcus lactis. We have determined the structures of several phage virions by electron microscopy, and that of the anti-receptors or baseplate (sets of 1-2 Mda), eventually complexed to their receptor, by X-ray diffraction. Still in the field of virology, we have recently launched  a project on the human hepatitis E virus (HEV).

With regard to bacterial infections, we have tackled the study of bacterial secretory systems, in particular those of type VI (T6SS) and type 9 (T9SS). We have determined the structure and interactions of some of the 13 components of T6SS. We aim to reconstruct the entire system using a “hybrid” approach including electron microscopy and X-ray diffraction. The same approach is applied to T9SS.

Alain Roussel’s Research topicPutting structural studies at the service of a detailed understanding of the mechanisms of life.

The studies we conduct focus on one hand on factors of pathogenicity of bacteria and on the other hand on means of response of host organisms. Our projects can be grouped in 2 scientific disciplines which are immunology and microbiology. 

At the methodological level, X-ray crystallography will remain the basis of all our studies but we are aware of the current developments in the field of structural biology. In particular, the rise of electron microscopy is opening up new avenues. We are also running a camelid antibody generation platform (also called VHH or Nanobody). This tool gives us a significant competitive advantage in tackling most of our projects.

Extracellular vesicles covered by recombinant Ebola GP

Adeline Goulet’s Research topicUnraveling the molecular mechanisms used by bacteriophages to infect their host

Bacteriophages (phages) are the most abundant biological entities on Earth. Yet, these sophisticated bacteria-killing nanomachines remain poorly understood. What has made them so successful?

Our main research interest is, in a pan-phage approach, to unravel the molecular mechanisms deployed by phages upon infection to recognize, puncture, and hijack their host. We use a multi-disciplinary approach including cryo-electron microscopy, X-ray crystallography, and biochemical/biophysical characterization of macromolecular interactions. With these combined investigations we aim to obtain multi-scale information on phage infection modus operandi. This provides us with a comprehensive understanding of phage-bacteria interactions, but not only that, as this knowledge will pave the way towards rational development of phage-based applications for therapeutic, diagnostic and biocontrol purposes.

Reconstruction of the p2 phage in the “resting” and “activated” forms

Isabelle Imbert’s Research topicIdentifying the molecular mechanisms of replication of RNA viruses

RNA viruses are responsible for all emerging infectious diseases (Ebola, Zika, Dengue, Coronaviruses…). Unfortunately, most of the time, we have few weapons to fight them, due to a certain lack of knowledge of their propagation cycle.
Combining multidisciplinary approaches such as biochemistry, enzymology, structural biology combining to artificial intelligence methods, we aim to dissect fascinating RNA virus replication machineries. These data will lay the groundwork for the discovery of anti-viral molecules. Indeed, viral replicases have already proved their worth with, for example, the development of therapies against HIV and HCV.

Model of SARS-CoV processive replication complex

Philippe Leone’s Research topicBacterial secretion system and nematode innate immunity.

Type IX Secretion System (T9SS)

The T9SS is responsible for Porphyromonas gingivalis pathogenesis through secretion of virulence factors, and for Flavobacterium johnsoniae motility through secretion of adhesins. Among the 18 identified proteins that are involved in T9SS function, the K-L-M-N proteins are supposed to form the core complex. We propose that the outer membrane ring-shaped K-N complex serves as an interaction platform to recruit the inner membrane L-M complex, and that the L-M complex is a novel rotary motor driven by proton motive force. Our objective is to solve the structures of the isolated soluble domains of L and N proteins, and of the L-M and K-L-M-N membrane complexes from the two bacterial models, by X-ray crystallography and cryo-EM (in collaboration with Olivier Lambert, ICBMN, Bordeaux). The function of the L-M complex, and notably its role as a rotary motor, will be addressed by in vivo approaches (in collaboration with Eric Cascales, LISM, Marseille).

Scheme of the T9SS in a Gram negative bacteria

C. elegans innate immunity

This project, in collaboration with Jonathan Ewbank (CIML, Marseille), aims at deciphering the host-pathogen relationships between C. elegans and the obligate fungal pathogen Drechmeria coniospora. By RNAi screening on whole C. elegans genome, our collaborators identified 270 genes involved in the nematode innate immunity. Among them, only 33 have no functional annotation, and even fewer are specific to nematodes and are not present in other metazoans. On the other hand, virulence factors from D. coniospora were identified and those not present in other fungi and without functional annotation were selected. Our objective is to solve the structures of the nematode and D. coniospora specific proteins; functional studies are carried out in parallel by our collaborators.

Publications

2022
A structural discovery journey of streptococcal phages adhesion devices by AlphaFold2

Adeline Goulet, Raphaela Joos, Katherine Lavelle, Douwe van Sinderen, Jennifer Mahony, Christian Cambillau

Frontiers in Molecular Biosciences 9 (2022)10.3389/fmolb.2022.960325

2022
Replication of the coronavirus genome: A paradox among positive-strand RNA viruses

Emeline Grellet, India l'Hôte, Adeline Goulet, Isabelle Imbert

Journal of Biological Chemistry 298:101923 (2022)10.1016/j.jbc.2022.101923

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2022
A truncated anti-CRISPR protein prevents spacer acquisition but not interference

Cécile Philippe, Carlee Morency, Pier-Luc Plante, Edwige Zufferey, Rodrigo Achigar, Denise M Tremblay, Geneviève M Rousseau, Adeline Goulet, Sylvain Moineau

Nature Communications 13 (2022)10.1038/s41467-022-30310-x

2021
Anchoring the T6SS to the cell wall: Crystal structure of the peptidoglycan binding domain of the TagL accessory protein

van Son Nguyen, Silvia Spinelli, E. Cascales, Alain Roussel, Christian Cambillau, Philippe Leone

PLoS ONE 16:e0254232 (2021)10.1371/journal.pone.0254232

2020
Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

Daniel Agudelo, Sophie Carter, Minja Velimirovic, Alexis Duringer, Jean-François Rivest, Sébastien Levesque, Jérémy Loehr, Mathilde Mouchiroud, Denis Cyr, Paula Waters, Mathieu Laplante, Sylvain Moineau, Adeline Goulet, Yannick Doyon

Genome Research 30:107-117 (2020)10.1101/gr.255414.119

2020
2020
Diversity of molecular mechanisms used by anti-CRISPR proteins: the tip of an iceberg?

Pierre Hardouin, Adeline Goulet

Biochemical Society Transactions 48:507-516 (2020)10.1042/BST20190638

2020
Revisiting the host adhesion determinants of Streptococcus thermophilus siphophages

Katherine Lavelle, Adeline Goulet, Brian Mcdonnell, Silvia Spinelli, Douwe Van Sinderen, Jennifer Mahony, Christian Cambillau

Microbial Biotechnology 13:1765-1779 (2020)10.1111/1751-7915.13593

2020
Wine phenolic compounds differently affect the host-killing activity of two lytic bacteriophages infecting the lactic acid bacterium oenococcus oeni

Cécile Philippe, Amel Chaib, Fety Jaomanjaka, Stéphanie Cluzet, Aurélie Lagarde, Patricia Ballestra, Alain Decendit, Melina Petrel, Olivier Claisse, Adeline Goulet, Christian C. Cambillau, Claire Le Marrec

Viruses 12:1-19 (2020)10.3390/v12111316

2020
Structural Insights into Lactococcal Siphophage p2 Baseplate Activation Mechanism

Silvia Spinelli, Denise Tremblay, Sylvain Moineau, Christian Cambillau, Adeline Goulet

Viruses 12 (2020)10.3390/v12080878

2019
Substrate binding mode and catalytic mechanism of human heparan sulfate d-glucuronyl C5 epimerase

Claire Debarnot, Yoan Monneau, Veronique Roig-Zamboni, Vincent Delauzun, Christine Le Narvor, Emeline Richard, Jérôme Hénault, Adeline Goulet, Firas Fadel, Romain R Vivès, Bernard Priem, David Bonnaffé, Hugues Lortat-Jacob, Yves Bourne

Proceedings of the National Academy of Sciences of the United States of America 116:6760-6765 (2019)10.1073/pnas.1818333116

2019
Cas9 Allosteric Inhibition by the Anti-CRISPR Protein AcrIIA6

Olivier Fuchsbauer, Paolo Swuec, Claire Zimberger, Beatrice Amigues, Sébastien Levesque, Daniel Agudelo, Alexis Duringer, Antonio Chaves-Sanjuan, Silvia Spinelli, Geneviève Rousseau, Minja Velimirovic, Martino Bolognesi, Alain Roussel, Christian Cambillau, Sylvain Moineau, Yannick Doyon, Adeline Goulet

Molecular Cell 76:922-937.e7 (2019)10.1016/j.molcel.2019.09.012

2018
Structure–Function Analysis of the C-Terminal Domain of the Type VI Secretion TssB Tail Sheath Subunit

Badreddine Douzi, Laureen Logger, Silvia Spinelli, Stephanie Blangy, Christian Cambillau, E. Cascales

Journal of Molecular Biology 430:297-309 (2018)10.1016/j.jmb.2017.11.015

2018
Type IX secretion system PorM and gliding machinery GldM form extended arches spanning the periplasmic space

Philippe Leone, Jennifer Roche, Maxence S Vincent, Quang Hieu Tran, Aline Desmyter, E. Cascales, Christine Kellenberger, Christian Cambillau, Alain Roussel

Nature Communications 9 (2018)10.1038/s41467-017-02784-7

2018
Towards a complete structural deciphering of Type VI secretion system

van Son Nguyen, Badreddine Douzi, Eric Durand, Alain Roussel, E. Cascales, Christian Cambillau

Current Opinion in Structural Biology 49:77-84 (2018)10.1016/j.sbi.2018.01.007

2018
The gp27-like Hub of VgrG Serves as Adaptor to Promote Hcp Tube Assembly

Melvin G Renault, Jordi Zamarreño Beas, Badreddine Douzi, Maïalène Chabalier, Abdelrahim Zoued, Yannick R Brunet, Christian Cambillau, Laure Journet, E. Cascales

Journal of Molecular Biology 430:3143-3156 (2018)10.1016/j.jmb.2018.07.018

2017
Unraveling the Self-Assembly of the Pseudomonas aeruginosa XcpQ Secretin Periplasmic Domain Provides New Molecular Insights into Type II Secretion System Secreton Architecture and Dynamics

Badreddine Douzi, Nhung Trinh, Sandra Michel-Souzy, Aline Desmyter, Genevieve Ball, Pascale Barbier, Artemis Kosta, Eric Durand, Katrina Forest, Christian Cambillau, Alain Roussel, Romé Voulhoux

mBio 8 (2017)10.1128/mBio.01185-17

2017
Type VI secretion TssK baseplate protein exhibits structural similarity with phage receptor-binding proteins and evolved to bind the membrane complex

van Son Nguyen, Laureen Logger, Silvia Spinelli, Pierre Legrand, Thi Thanh Huyen Pham, Thi Trang Nhung Trinh, Yassine Cherrak, Abdelrahim Zoued, Aline Desmyter, Eric Durand, Alain Roussel, Christine Kellenberger, E. Cascales, Christian Cambillau

Nature Microbiology 2:17103 (2017)10.1038/nmicrobiol.2017.103

2017
Characterization of the Porphyromonas gingivalis Type IX Secretion Trans-envelope PorKLMNP Core Complex

Maxence S Vincent, Mickaël J Canestrari, Philippe Leone, Julien Stathopulos, Bérengère Ize, Abdelrahim Zoued, Christian Cambillau, Christine Kellenberger, Alain Roussel, E. Cascales

Journal of Biological Chemistry 292:3252-3261 (2017)10.1074/jbc.M116.765081

2017
TssA: The cap protein of the Type VI secretion system tail

Abdelrahim Zoued, Eric Durand, Yoann G Santin, Laure Journet, Alain Roussel, Christian Cambillau, E. Cascales

BioEssays 39 (2017)10.1002/bies.201600262

2016
Structure and specificity of the Type VI secretion system ClpV-TssC interaction in enteroaggregative Escherichia coli

Badreddine Douzi, Yannick R Brunet, Silvia Spinelli, Valentine Lensi, Stephanie Blangy, Anant Kumar, Laure Journet, Pierre Legrand, E. Cascales, Christian Cambillau

Scientific Reports 6 (2016)10.1038/srep34405

2016
A phospholipase A 1 antibacterial Type VI secretion effector interacts directly with the C-terminal domain of the VgrG spike protein for delivery

Nicolas Flaugnatti, Thi Thu Hang Le, Stéphane Canaan, Marie-Stéphanie Aschtgen, Vân Nguyên, Stephanie Blangy, Christine Kellenberger, Alain Roussel, Christian Cambillau, E. Cascales, Laure Journet

Molecular Microbiology 99:1099-1118 (2016)10.1111/mmi.13292

2016
Priming and polymerization of a bacterial contractile tail structure. 1" 2" 17

Abdelrahim Zoued, Eric Durand, Yannick R Brunet, Silvia Spinelli, Badreddine Douzi, Mathilde Guzzo, Nicolas Flaugnatti, Pierre Legrand, Laure Journet, Rémi Fronzes, Tam Mignot, Christian Cambillau, E. Cascales

Nature 531:59-63 (2016)10.1038/nature17182

2016
Structure–Function Analysis of the TssL Cytoplasmic Domain Reveals a New Interaction between the Type VI Secretion Baseplate and Membrane Complexes

Abdelrahim Zoued, Chloé J Cassaro, Eric Durand, Badreddine Douzi, Alexandre España, Christian Cambillau, Laure Journet, E. Cascales

Journal of Molecular Biology 428:4413-4423 (2016)10.1016/j.jmb.2016.08.030

2015
Biogenesis and structure of a Type VI secretion membrane core complex

Eric Durand, van Son Nguyen, Abdelrahim Zoued, Laureen Logger, Gerard Pehau-Arnaudet, Marie-Stéphanie Aschtgen, Silvia Spinelli, Aline Desmyter, Benjamin Bardiaux, Annick Dujeancourt, Alain Roussel, Christian Cambillau, E. Cascales, Rémi Fronzes

Nature 523:555-560 (2015)10.1038/nature14667

2015
Inhibition of Type VI Secretion by an Anti-TssM Llama Nanobody

van Son Nguyen, Laureen Logger, Silvia Spinelli, Aline Desmyter, Thi Thu Hang Le, Christine Kellenberger, Badreddine Douzi, Eric Durand, Alain Roussel, E. Cascales, Christian Cambillau

PLoS ONE 10:1-14 (2015)

2015
Production, crystallization and X-ray diffraction analysis of a complex between a fragment of the TssM T6SS protein and a camelid nanobody

van Son Nguyen, Silvia Spinelli, Aline Desmyter, Thi Thu Hang Le, Christine Kellenberger, E. Cascales, Christian Cambillau, Alain Roussel

Acta crystallographica Section F : Structural biology communications [2014-...] 71:266-271 (2015)10.1107/S2053230X15000709

2015
Crystallization and preliminary X-ray analysis of the C-terminal fragment of PorM, a subunit of the Porphyromonas gingivalis type IX secretion system

Julien Stathopulos, Christian Cambillau, E. Cascales, Alain Roussel, Philippe Leone

Acta crystallographica Section F : Structural biology communications [2014-...] 71:71-74 (2015)10.1107/S2053230X1402559X

2014
Crystal Structure and Self-Interaction of the Type VI Secretion Tail-Tube Protein from Enteroaggregative Escherichia coli

Badreddine Douzi, Silvia Spinelli, Stéphanie Blangy, Alain Roussel, Eric Durand, Yannick Brunet, E. Cascales, Christian Cambillau

PLoS ONE 9:e86918 (2014)10.1371/journal.pone.0086918

2014
VgrG, Tae, Tle, and beyond: the versatile arsenal of Type VI secretion effectors.

Eric Durand, Christian Cambillau, E. Cascales, Laure Journet

Trends Microbiol. 22:498-507 (2014)10.1016/j.tim.2014.06.004

2014
VgrG, Tae, Tle, and beyond: the versatile arsenal of Type VI secretion effectors

Eric Durand, Christian Cambillau, E. Cascales, Laure Journet

Trends in Microbiology 22:498-507 (2014)10.1016/j.tim.2014.06.004

2014
Architecture and assembly of the Type VI secretion system

Abdelrahim Zoued, Yannick Brunet, Eric Durand, Marie-Stéphanie Aschtgen, Laureen Logger, Badreddine Douzi, Laure Journet, Christian Cambillau, E. Cascales

Biochimica et Biophysica Acta - Molecular Cell Research 1843:1664-1673 (2014)10.1016/j.bbamcr.2014.03.018

2014
Architecture and assembly of the Type VI secretion system.

Abdelrahim Zoued, Yannick R Brunet, Eric Durand, Marie-Stéphanie Aschtgen, Laureen Logger, Badreddine Douzi, Laure Journet, Christian Cambillau, E. Cascales

Biochim. Biophys. Acta 1843:1664-73 (2014)10.1016/j.bbamcr.2014.03.018

2013
Biochemical and structural characterization of non-glycosylated Yarrowia lipolytica LIP2 lipase

Ahmed Aloulou, Anaïs Bénarouche, Delphine Puccinelli, Silvia Spinelli, Jean-François Cavalier, Christian Cambillau, Frédéric Carrière

European Journal of Lipid Science and Technology 115:429-441 (2013)10.1002/ejlt.201200440

2013
Dissection of the TssB-TssC Interface during Type VI Secretion Sheath Complex Formation

Xiang Y. Zhang, Yannick R Brunet, Laureen Logger, Badreddine Douzi, Christian Cambillau, Laure Journet, E. Cascales

PLoS ONE 8:e81074 (2013)10.1371/journal.pone.0081074

2013
TssK Is a Trimeric Cytoplasmic Protein Interacting with Components of Both Phage-like and Membrane Anchoring Complexes of the Type VI Secretion System

Abdelrahim Zoued, Eric Durand, Cecilia C. Bebeacua, Yannick R Brunet, Badreddine Douzi, Christian Cambillau, E. Cascales, Laure Journet

Journal of Biological Chemistry 288:27031-27041 (2013)10.1074/jbc.M113.499772

2012
Structural biology of type VI secretion systems

E. Cascales, Christian Cambillau

Philosophical Transactions of the Royal Society B: Biological Sciences 367:1102-1111 (2012)10.1098/rstb.2011.0209

2012
Structural biology of type VI secretion systems.

E. Cascales, Christian Cambillau

Philos. Trans. R. Soc. Lond., B, Biol. Sci. 367:1102-11 (2012)10.1098/rstb.2011.0209

2012
Crystal structure of the VgrG1 actin cross-linking domain of the Vibrio cholerae type VI secretion system.

Eric Durand, Estelle Derrez, Gilles Audoly, Silvia Spinelli, Miguel Ortiz-Lombardia, Didier Raoult, E. Cascales, Christian Cambillau

Journal of Biological Chemistry 287:38190-9 (2012)10.1074/jbc.M112.390153

2012
Structural characterization and oligomerization of the TssL protein, a component shared by bacterial type VI and type IVb secretion systems.

Eric Durand, Abdelrahim Zoued, Silvia Spinelli, Paul J H Watson, Marie-Stéphanie Aschtgen, Laure Journet, Christian Cambillau, E. Cascales

Journal of Biological Chemistry 287:14157-68 (2012)10.1074/jbc.M111.338731

2012
Crystal Structure of the VgrG1 Actin Cross-linking Domain of the Vibrio cholerae Type VI Secretion System

Eric Durand, Estelle Derrez, Gilles Audoly, Silvia Spinelli, Miguel Ortiz-Lombardia, Didier Raoult, E. Cascales, Christian Cambillau

Journal of Biological Chemistry 287:38190-38199 (2012)10.1074/jbc.M112.390153

2011
Deciphering the Xcp Pseudomonas aeruginosa type II secretion machinery through multiple interactions with substrates.

Badreddine Douzi, Geneviève Ball, Christian Cambillau, Mariella Tegoni, Romé Voulhoux

Journal of Biological Chemistry 286:40792-801 (2011)10.1074/jbc.M111.294843

2011
Towards a Structural Comprehension of Bacterial Type VI Secretion Systems: Characterization of the TssJ-TssM Complex of an Escherichia coli Pathovar

Catarina Felisberto-Rodrigues, Eric Durand, Marie-Stéphanie Aschtgen, Stéphanie Blangy, Miguel Ortiz-Lombardia, Badreddine Douzi, Christian Cambillau, E. Cascales

PLoS Pathogens 7:e1002386 (2011)10.1371/journal.ppat.1002386

2011
Towards a structural comprehension of bacterial type VI secretion systems: characterization of the TssJ-TssM complex of an Escherichia coli pathovar

Catarina Felisberto-Rodrigues, Eric Durand, Marie-Stéphanie Aschtgen, Stephanie Blangy, Miguel Ortiz-Lombardia, Badreddine Douzi, Christian Cambillau, E. Cascales

PLoS Pathogens 7:e1002386 (2011)10.1371/journal.ppat.1002386

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Collaborations

  • National
    • Dr Eric Cascales, LISM, Marseille
    • Dr Olivier Lambert, CBMN, Bordeaux
  • International

Funding

© 2022 LISM - Laboratoire d'Ingénierie des Systèmes Macromoléculaires - CNRS UMR7255

31 Chemin Joseph Aiguier, 13402 Marseille cedex 20, France