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ComBact SIGNED

How complement molecules kill bacteria

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Project "ComBact" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITAIR MEDISCH CENTRUM UTRECHT 

Organization address
address: HEIDELBERGLAAN 100
city: UTRECHT
postcode: 3584 CX
website: www.umcutrecht.nl

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Netherlands [NL]
 Project website http://www.evasionutrecht.nl/staff/suzan-rooijakkers/
 Total cost 1˙497˙290 €
 EC max contribution 1˙497˙290 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-STG
 Funding Scheme ERC-STG
 Starting year 2015
 Duration (year-month-day) from 2015-03-01   to  2020-02-29

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITAIR MEDISCH CENTRUM UTRECHT NL (UTRECHT) coordinator 1˙497˙290.00

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 Project objective

This proposal aims to provide insight into how bacteria are killed by the complement system, an important part of the host immune response against bacterial infections. Complement is a large protein network in plasma that labels bacteria for phagocytosis and directly kills them via the formation of a pore-forming complex (Membrane Attack Complex (MAC)). Currently we do not understand how complement activation results in bacterial killing. This knowledge gap is mainly caused by the lack of tools to study the enzymes that trigger MAC formation: the C5 convertases.

In my lab, we recently established a novel assay system for C5 convertases that allows us for the first time to study these enzymes under purified conditions. This model, combined with my expertise in microbiology, places my lab in a unique position to understand C5 convertase biology (Aim 1), determine the enzyme's role in MAC functioning (Aim 2) and elucidate how the MAC kills bacteria (Aim 3). Thus, I aim to provide insight into the molecular events necessary for bacterial killing by the complement system.

I will use biochemical, structural and microbiological approaches to elucidate the precise molecular arrangement of C5 convertases in vitro and on bacterial cells. I will generate unique tools to study how C5 convertases regulate MAC insertion into bacterial membranes. Finally, I will engineer fluorescent bacteria and labeled complement proteins to perform advanced microscopy analyses of how MAC kills bacteria.

These insights will lead to fundamental knowledge about the functioning of complement and will create new avenues for blocking the undesired complement activation during systemic infections and acute inflammatory processes. Furthermore this knowledge will improve desired complement activation by therapeutic antibodies and vaccination strategies in infectious diseases. Finally, this work opens up new possibilities to understand how both humans and bacteria regulate complement.

 Publications

year authors and title journal last update
List of publications.
2019 Dennis J Doorduijn, Bart W Bardoel, Dani AC Heesterbeek, Maartje Ruyken, Georgina Benn, Edward S Parsons, Bart Hoogenboom, Suzan HM Rooijakkers
Bacterial killing by complement requires direct anchoring of Membrane Attack Complex precursor C5b-7
published pages: , ISSN: , DOI: 10.1101/2019.12.17.877639
Review Commons 2020-04-24
2020 Dani A. C. Heesterbeek, Remy M. Muts, Vincent P. van Hensbergen, Pieter de Saint Aulaire, Tom Wennekes, Bart W. Bardoel, Nina M. van Sorge, Suzan H.M. Rooijakkers
Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
published pages: , ISSN: , DOI: 10.1101/2020.01.28.923243
Review Commons 2020-04-24
2018 Dani Heesterbeek
Type: Poster presentation – selected abstractDescription: Poster presentation at the Dutch Complement Symposium 2018Title: “Bacterial killing by complement requires membrane attack complex formation via surface-bound C5-convertases”
published pages: , ISSN: , DOI:
2019-10-29
2018 Seline Zwarthoff
Type: Poster presentationDescription: Presentation at Keystone Symposia, Antibodies as Drugs: Translating Molecules into Treatments (C1), Whistler, CanadaTitle: Proteases C1r and C1s regulate binding of C1q to certain human IgG subclasses
published pages: , ISSN: , DOI:
2019-10-29
2018 Dani Heesterbeek
Type: Oral presentationDescription: Presentation at the Science for life symposium, Utrecht, 2018Title: “The role of C5 convertases in MAC dependent killing of Gram-negative bacteria”
published pages: , ISSN: , DOI:
2019-10-29
2019 Dennis J Doorduijn
Oral presentationDescription: Presentation at the Scientific Spring Meeting KNVM & NVMM 2019Title: \'Molecular insights into the killing of E. coli by Membrane Attack Complex pores’
published pages: , ISSN: , DOI:
2019-10-29
2019 Seline Zwarthoff
Type: Oral presentationDescription: Presentation at KNVM & NVMM Scientific Spring meeting 2019, ArnhemTitle: Proteases C1r and C1s affect binding of C1q to certain human IgG subclasses
published pages: , ISSN: , DOI:
2019-10-29
2019 Dani Heesterbeek
Type: Oral presentation – for kiem award Description: Presentation at the Scientific Spring Meeting of the Dutch Society of Microbiology (NVMM & KNVM)Title: “Bacterial killing by complement requires membrane attack complex formation via surface-bound C5-convertases”
published pages: , ISSN: , DOI:
2019-10-29
2018 Bart Bardoel
Type: Oral presentationDescription: Prato pores conference 2018’Title: “The human complement system sensitizes Gram-negative bacteria for Gram-positive-specific antibiotics via pore formation in the outer membrane”
published pages: , ISSN: , DOI:
2019-10-29
2019 Seline Abigaïl Zwarthoff
How antibodies drive complement activation Paving the road towards effective therapeutics
published pages: , ISSN: , DOI:
2019-10-29
2018 Seline Zwarthoff
Type: Poster presentationDescription: Presentation at Dutch Complement Symposium, Nunspeet, The NetherlandsTitle: Proteases C1r and C1s affect binding of C1q to certain human IgG subclasses
published pages: , ISSN: , DOI:
2019-10-29
2019 Dani Heesterbeek
Type: Poster presentation – selected abstractDescription: Poster presentation at the EMBL conference: new concepts and approaches in microbiologyTitle: “Generation of a fluorescent reporter system in E. coli to study bacterial membrane damage by the immune system”
published pages: , ISSN: , DOI:
2019-10-29
2018 Seline Zwarthoff
Type: Poster presentationDescription: Presentation at Science for Life Conference, Utrecht, the Netherlands Title: Proteases C1r and C1s affect binding of C1q to certain human IgG subclasses
published pages: , ISSN: , DOI:
2019-10-29
2018 Fernanda L. Paganelli, Helen L. Leavis, Samantha He, Nina M. van Sorge, Christine Payré, Gérard Lambeau, Rob J. L. Willems, Suzan H. M. Rooijakkers
Group IIA-Secreted Phospholipase A 2 in Human Serum Kills Commensal but Not Clinical Enterococcus faecium Isolates
published pages: , ISSN: 0019-9567, DOI: 10.1128/iai.00180-18
Infection and Immunity 86/8 2019-10-10
2017 DAC Heesterbeek
oral presentation: The role of convertases in MACdependent killing of bacteria
published pages: , ISSN: , DOI:
2019-10-10
2019 Dani A. C. Heesterbeek
how complement kills bacteria: a pore way to die
published pages: , ISSN: , DOI:
2019-10-10
2019 S Zwarthoff
oral presentation: Proteases C1r and C1s affect binding of C1q to certain human IgG subclasses
published pages: , ISSN: , DOI:
2019-10-10
2019 D. A. C. Heesterbeek, N. I. Martin, A. Velthuizen, M. Duijst, M. Ruyken, R. Wubbolts, S. H. M. Rooijakkers, B. W. Bardoel
Complement-dependent outer membrane perturbation sensitizes Gram-negative bacteria to Gram-positive specific antibiotics
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-019-38577-9
Scientific Reports 9/1 2019-10-10
2018 Dani A.C. Heesterbeek, Mathieu L. Angelier, Richard A. Harrison, Suzan H.M. Rooijakkers
Complement and Bacterial Infections: From Molecular Mechanisms to Therapeutic Applications
published pages: 455-464, ISSN: 1662-811X, DOI: 10.1159/000491439
Journal of Innate Immunity 10/5-6 2019-10-10
2018 Nienke W. M. de Jong, Manouk Vrieling, Brandon L. Garcia, Gerrit Koop, Matt Brettmann, Piet C. Aerts, Maartje Ruyken, Jos A. G. van Strijp, Mark Holmes, Ewan M. Harrison, Brian V. Geisbrecht, Suzan H. M. Rooijakkers
Identification of a staphylococcal complement inhibitor with broad host specificity in equid Staphylococcus aureus strains
published pages: 4468-4477, ISSN: 0021-9258, DOI: 10.1074/jbc.RA117.000599
Journal of Biological Chemistry 293/12 2019-10-10
2018 Seline A. Zwarthoff, Evelien T. M. Berends, Sanne Mol, Maartje Ruyken, Piet C. Aerts, Mihály Józsi, Carla J. C. de Haas, Suzan H. M. Rooijakkers, Ronald D. Gorham
Functional Characterization of Alternative and Classical Pathway C3/C5 Convertase Activity and Inhibition Using Purified Models
published pages: , ISSN: 1664-3224, DOI: 10.3389/fimmu.2018.01691
Frontiers in Immunology 9 2019-10-10
2019 Dennis J. Doorduijn, Suzan H. M. Rooijakkers, Dani A. C. Heesterbeek
How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria
published pages: 1900074, ISSN: 0265-9247, DOI: 10.1002/bies.201900074
BioEssays 41/10 2019-10-10
2019 D J Doorduijn
Bacterial killing by MAC pores requires immediate assembly of C5b-7
published pages: , ISSN: , DOI:
2019-10-10
2017 SHM Rooijakkers
invited lecture: Complement as a recognition molecule system
published pages: , ISSN: , DOI:
2019-10-10
2017 Bart Bardoel
oral presentation: Complement sensitizes Gram-negativebacteria for Gram-positive-specific antibiotics
published pages: , ISSN: , DOI:
2019-10-10
2018 Bart Bardoel (replacing Suzan Rooijakkers)
invited lecture: Molecular insights into complement-mediated killing of Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-10-10
2019 DAC Heesterbeek
oral presentation: Disruption of Gram-negative bacteria by human serum requires complement and lysozyme
published pages: , ISSN: , DOI:
2019-10-10
2018 Dennis Doorduijn
oral presentation: Surface-bound enzymes facilitate pore formation by the Membrane Attack Complex to efficiently kill Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-10-10
2019 Heesterbeek, D. A.; Bardoel, B. W.; Parsons, E. S.; Bennett, I.; Ruyken, M.; Doorduijn, D. J.; Gorham, R. D.; Berends, E. T.; Pyne, A. L.; Hoogenboom, B. W.; Rooijakkers, S. H.
Bacterial killing by complement requires membrane attack complex formation via surface-bound C5 convertases
published pages: , ISSN: 1460-2075, DOI: 10.15252/embj.201899852
EMBO Journal , Article e99852. (2019) (In press). 1 2019-10-10
2019 S.H.M. Rooijakkers
Invited lecture: Antibody-mediated killing of bacteria by complement
published pages: , ISSN: , DOI:
2019-10-10
2018 SHM Rooijakkers
invited lecture: Antibody‐Mediated Killing ofBacteria by Complement
published pages: , ISSN: , DOI:
2019-10-10
2017 Seline Zwarthoff
\"Oral presentation: \"\"Defining the molecular interplay between antibodies and complement in bacterial infections\"\"\"
published pages: , ISSN: , DOI:
2019-05-29
2017 Daphne A.C. Stapels, Jordan L. Woehl, Fin J. Milder, Angelino T. Tromp, Aernoud A. van Batenburg, Wilco C. de Graaf, Samuel C. Broll, Natalie M. White, Suzan H.M. Rooijakkers, Brian V. Geisbrecht
Evidence for Multiple Modes of Neutrophil Serine Protease Recognition by the EAP Family of Staphylococcal Innate Immune Evasion Proteins
published pages: , ISSN: 0961-8368, DOI: 10.1002/pro.3342
Protein Science 2019-05-29
2016 Fernanda L. Paganelli
Oral presentationTitle: Genome-wide screening identifies PTS permease BepA to be involved in Enterococcus faecium endocarditis and biofilm formation.
published pages: , ISSN: , DOI:
2019-05-29
2016 Dani Heesterbeek
Oral presentation: The role of C5 convertases in MAC-dependent killing of Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-05-29
2016 Fernanda L. Paganelli
Oral presentation: YajC Promotes Enterococcus faecium and Staphylococcus aureus Biofilm Formation by Retaining Intracellular Protein at the Bacterial Surface
published pages: , ISSN: , DOI:
2019-05-29
2016 Brandon L. Garcia, Seline A. Zwarthoff, Suzan H. M. Rooijakkers, Brian V. Geisbrecht
Novel Evasion Mechanisms of the Classical Complement Pathway
published pages: 2051-2060, ISSN: 0022-1767, DOI: 10.4049/jimmunol.1600863
The Journal of Immunology 197/6 2019-05-29
2016 Suzan Rooijakkers
\"Invited lecture: \"\"How the human complement system kills bacteria\"\".\"
published pages: , ISSN: , DOI:
2019-05-29
2017 Ron D Gorham Jr
Poster presentation: Functional characterization of alternative pathway C3 and C5 convertase inhibitors
published pages: , ISSN: , DOI:
2019-05-29
2017 Dennis Doorduijn
Poster presentation: Creating model systems to study molecular mechanisms of C5-convertase-induced Membrane Attack Complex assembly
published pages: , ISSN: , DOI:
2019-05-29
2017 Bart Bardoel
Poster presentation: Complement sensitizes Gram-negative bacteria for gram-positive specific antibiotics
published pages: , ISSN: , DOI:
2019-05-29
2017 Dani Heesterbeek
Oral presentation: C5 convertases in MAC-dependent killing of Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-05-29
2016 Seline Zwarthoff
Oral presentation: Mimicking classical complement activation in purified model systems
published pages: , ISSN: , DOI:
2019-05-29
2017 Suzan Rooijakkers
\"Invited lecture: \"\"Complement Activation as a target for combating infections\"\"\"
published pages: , ISSN: , DOI:
2019-05-29
2015 Bart Bardoel
Poster presentation
published pages: , ISSN: , DOI:
2019-05-29
2017 Dennis Doorduijn
Poster presentation: A liposome model to study structural and functional aspects of the Membrane Attack Complex in complex with a C5-convertase
published pages: , ISSN: , DOI:
2019-05-29
2017 Dani Heesterbeek
Oral presentation: C5 convertases drive MAC-dependent killing of Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-05-29
2015 Suzan Rooijakkers
Invited lecture: How Staphylococcus aureus escapes the immune system.
published pages: , ISSN: , DOI:
2019-05-29
2015 Daphne Stapels
Immune-evasion of Staphylococcus aureus via its extracellular adherence proteins
published pages: , ISSN: , DOI:
2019-05-29
2016 Suzan Rooijakkers
\"Keynote lecture at the Florey symposium for host-pathogen interactions. \"\"Molecular interplay between complement and bacteria\"\".\"
published pages: , ISSN: , DOI:
2019-05-29
2016 Suzan Rooijakkers
\"Invited lecture: \"\"Enhancing complement activation on bacteria\"\".\"
published pages: , ISSN: , DOI:
2019-05-29
2017 Elise S. Hovingh, Bryan van den Broek, Betsy Kuipers, Elena Pinelli, Suzan H. M. Rooijakkers, Ilse Jongerius
Acquisition of C1 inhibitor by Bordetella pertussis virulence associated gene 8 results in C2 and C4 consumption away from the bacterial surface
published pages: e1006531, ISSN: 1553-7374, DOI: 10.1371/journal.ppat.1006531
PLOS Pathogens 13/7 2019-05-29
2016 Ron D Gorham Jr
Poster presentation: Elucidating the molecular mechanisms of complement-mediated neutrophil phagocytosis
published pages: , ISSN: , DOI:
2019-05-29
2017 Seline Zwarthoff
Poster presentation: Defining the molecular interplay between antibodies and complement in bacterial infections
published pages: , ISSN: , DOI:
2019-05-29
2016 Seline Zwarthoff
Poster presentation: Mimicking classical complement activation in purified model systems
published pages: , ISSN: , DOI:
2019-05-29
2015 Evelien Berends
Molecular interplay between bacteria and the terminal complement pathway
published pages: , ISSN: , DOI:
2019-05-29
2016 Dani Heesterbeek
Oral presentation: Role of C5 convertases in MAC-dependent killing of Gram-negative bacteria
published pages: , ISSN: , DOI:
2019-05-29
2015 Suzan Rooijakkers
\"\"\"Complement activation on bacteria\"\"\"
published pages: , ISSN: , DOI:
2019-05-29
2016 Suzan Rooijakkers
Keynote lecture at the Dublin Academy for Pathogenomics and Infection Biology.
published pages: , ISSN: , DOI:
2019-05-29
2015 Ron D Gorham Jr
Poster presentation: Discovery of small molecules for fluorescent detection of complement activation product C3d
published pages: , ISSN: , DOI:
2019-05-29
2017 Ron D Gorham Jr
Oral presentation: Functional characterization of alternative pathway C3 and C5 convertase inhibitors
published pages: , ISSN: , DOI:
2019-05-29
2016 Ron D Gorham Jr
Poster presentation: molecular mechanisms of complement-mediated neutrophil phagocytosis
published pages: , ISSN: , DOI:
2019-05-29
2016 Bart Bardoel
Oral presentation: “Genome-wide CRISPR screen reveals novel host factors required for Staphylococcus aureus α-hemolysin-mediated toxicity”
published pages: , ISSN: , DOI:
2019-05-29
2017 Bart Bardoel
Oral presentation: “Complement sensitizes Gram-negative bacteria for “Gram-positive specific” antibiotics”
published pages: , ISSN: , DOI:
2019-05-29
2017 Kaila M. Bennett, Suzan H. M. Rooijakkers, Ronald D. Gorham
Let’s Tie the Knot: Marriage of Complement and Adaptive Immunity in Pathogen Evasion, for Better or Worse
published pages: , ISSN: 1664-302X, DOI: 10.3389/fmicb.2017.00089
Frontiers in Microbiology 8 2019-05-27
2016 Kuipers, A
Mechanisms to suppress or enhance phagocytosis of staphylococci
published pages: , ISSN: , DOI:
4 2019-05-27
2016 Dennis J. Doorduijn, Suzan H.M. Rooijakkers, Willem van Schaik, Bart W. Bardoel
Complement resistance mechanisms of Klebsiella pneumoniae
published pages: 1102-1109, ISSN: 0171-2985, DOI: 10.1016/j.imbio.2016.06.014
Immunobiology 221/10 2019-05-27
2015 Evelien T. M. Berends, Ronald D. Gorham, Maartje Ruyken, Jasper A. Soppe, Hatice Orhan, Piet C. Aerts, Carla J. C. de Haas, Piet Gros, Suzan H. M. Rooijakkers
Molecular insights into the surface-specific arrangement of complement C5 convertase enzymes
published pages: , ISSN: 1741-7007, DOI: 10.1186/s12915-015-0203-8
BMC Biology 13/1 2019-05-27
2016 Annemarie Kuipers, Daphne A. C. Stapels, Maartje Ruyken, Lleroy T. Weerwind, Suzan H. M. Rooijakkers, Jean C. Lee, Kok P. M. van Kessel, Ya-Ping Ko
The Staphylococcus aureus polysaccharide capsule and Efb-dependent fibrinogen shield act in concert to protect against phagocytosis
published pages: 1185-1194, ISSN: 1350-0872, DOI: 10.1099/mic.0.000293
Microbiology 162/7 2019-05-27

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