UMI HUB researchers novel discoveries
The bacterium Streptococcus pneumoniae is the principal cause of community-acquired pneumonia and can also cause ear infections, sinusitis, meningitis and sepsis. Antibiotics form the main line of defence against these infections, but resistance to them is rapidly evolving.
Researchers at the laboratory of Suzan Rooijakkers at the University Medical Centre Utrecht, have successfully showed that monoclonal antibodies against pneumococci can be effective, especially when they are modified. Read more here.
All cells in the body are scanned constantly by our own immune system. Healthy cells present small fragments of degraded proteins, as ‘self’ HLA peptide antigens, that are well-tolerated by our individual immune systems. Aberrant and cancerous cells, on the other hand, may present unique or mutated surface marks that can trigger T-cells to become activated. This surveillance through HLA peptide antigens forms the basis to trigger and modulate T-cell responses. Hence HLA peptide presentation can influence tumor clearance, and can also be exploited in tumor immunotherapy and vaccination. Here, researchers of Utrecht University, the UMCU and the Hubrecht Institute investigated clonal diversity in tumor-specific HLA peptide presentation, for fundamental rules to target tumors.
Tumor heterogeneity as major cause of therapeutic resistance
Tumors are not uniform, but a diverse collection of cells; some of these may resist treatment better than others and can survive toxic stress of chemical drugs to re-establish during cancer relapse. For many chemical drugs, this model of tumor evolution acting on intrinsic tumor heterogeneity is well-documented. It is not known, however, if HLA peptide presentation is also heterogenous. This knowledge will potentially help us to understand escape from immunosurveillance and from immunotherapy.
“A key question to address is whether tumor heterogeneity is also reflected in the antigens presented by tumor cells. This is an important question because if such heterogeneity exists, some tumor cells can still evade the immune system just like how drug-resistant cells evade regular therapy”, says Laura Demmers, PhD candidate at the Biomolecular Mass Spectrometry and Proteomics group.
Integrating technologies for deeper characterization of tumor surface presentation
This work required the initial tumor and normal single cells, from one colorectal cancer patient, to be preserved and amplified using the organoid platform, in collaboration with Hans Clevers at the Hubrecht Institute. This gave a boost to the detection of unique tumor HLA peptide antigens by alleviating the bottleneck of patient material scarcity.
HLA peptide antigens may be smaller fragments than proteins, but these short peptides are in no ways easier to characterize than whole-proteins. Such peptides from tumor cells may also harbor protein-coding mutations that further complicate their identification and the inference of their origin. To solve this, patient and tumor clone-specific sequencing was also performed in collaboration with Edwin Cuppen at the UMC Utrecht. The fundamental detection of HLA peptide antigens was further boosted by the complementary use of two fragmentation methods in the mass spectrometer, to capitalize on different chemical properties of diverse HLA peptide species.
This collaborative work between the researchers from the UMCU, UU and Hubrecht Institute was supported by the X-Omics National Roadmap Initiative (www.x-omics.nl) and the Utrecht Molecular Immunology Hub and the Gravitation Program Institute for Chemical Immunology.
The tumor-specific HLA peptide antigen landscape
The team at Utrecht University found that about 300 HLA peptide antigens were presented exclusively by the tumor cells. Many of these antigens originate from notorious oncogenic proteins and are shared amongst all tumor clones analysed. Such antigen targets are very interesting to pursue for personalized immunotherapy, and in theory should be equally effective against all tumor cells of the same patient.
More intriguingly, the HLA peptide repertoire between different tumor clones of the same individual also differed significantly by 15-25%, as the data suggested. Such variations in antigen presentation may be sufficient to drive immunotherapeutic escape, in mechanisms similar to the selection of resistant phenotypes in chemotherapy. To overcome this, targeting multiple antigens simultaneously may help, but better solutions may emerge while re-tracing the mechanistic path in HLA peptide antigen presentation.
While sieving through the antigens consistently presented only by tumor cells, the team found quite some fragments of DNA damage sensing and repair proteins, for instance, peptides from BRCA proteins. This made a lot sense in tumors, since getting rid of DNA repair mechanisms would allow accumulation of deleterious traits towards malignancy.
“The key to treat cancer lies in the jab we take at the Achilles’ heel”, says Wei Wu, Assistant Professor at the Department of Pharmaceutical Sciences, “while keeping DNA repair silent provides a huge advantage for tumors to progress, it inevitably exposes a weakness on the cell surface, that we can target. The same may also apply to other cancers, since loss of DNA repair is also conserved across many other cancers”.
“An aspect of the work I also like is that we use the organoid technology to actually amplify the signal of a single tumor cell, providing an alternative route for single cell proteomics”, says Albert Heck, Professor of Chemistry and Pharmaceutical Sciences at Utrecht University. This work takes on a new angle to perceive the ideal choice of cancer neoantigens. Instead of focusing on over-expressed oncogenic and mutated proteins, the authors propose that peptide fragments from the degradation of tumor suppressor proteins may also be relevant candidates.
This work was recently published in Nature Communications.
Discovering how viral infections reshape the structure, composition and metabolism of host cells has been a poignant topic of research. In particular, the group of enteroviruses contains many important pathogens for humans, including poliovirus, coxsackievirus, rhinovirus, as well as newly emerging global health threats such as EV-A71 and EV-D68. In a recently published paper, August 28th, 2020, Nature Communications, a collaborative effort between Utrecht Molecular Immunology Hub researchers (Frank van Kuppeveld, Esther Nolte-‘t Hoen (Faculty of Veterinary Medicine) and Albert Heck (Biomolecular Mass Spectrometry and Proteomics) at Utrecht University) have performed an unbiased, system-wide and time-resolved analysis of the proteome and phosphoproteome of human cells infected with coxsackievirus B3. Through this study, they identified several cellular signalling pathways that are important for enterovirus replication and spreading. The recent publication provides a rich framework for a system-level understanding of enterovirus-induced perturbations at the protein and signalling pathway levels, forming a base for the development of pharmacological inhibitors to treat enterovirus infections.
Covid-19 Corona virus
Press conference Berend-Jan Bosch 14 May 2020
The online press conference can be found by scrolling to the bottom of the linked page.Press Conference
Researchers at Utrecht University, Erasmus Medical Center, and Harbour BioMed (HBM) today reported that they have identified a fully human monoclonal antibody that prevents the SARS-CoV-2 (COVID-19) virus from infecting cultured cells. The discovery, published online today in Nature Communications, is an initial step towards developing a fully human antibody to treat or prevent the respiratory disease COVID-19 caused by the novel coronavirus SARS-CoV-2. This article has been published in Technology Networks and can be assessed here.
Utrecht Molecular Immunology Hub (UMI Hub) scientists and coronavirus experts, at both Utrecht University, the Erasmus Medical Center, and Harbour Biomed (HBM) reported that they have identified a fully human monoclonal antibody that prevents the SARS-CoV-2 (COVID-19) virus from infecting cultured cells. The discovery published online in Nature Communications is an initial step towards developing a fully human antibody to treat or prevent the respiratory disease COVID-19 caused by the novel coronavirus SARS-CoV-2. The full article is available here.
Associate professor at Utrecht University and UMI Hub scientist Berend-Jan Bosh who is also the co-lead author of the Nature communications study will further explain his research for journalists on May 14 at an online press conference to attend please mail, email@example.com.
Discovering how infectious viral diseases carried by animals can be transmitted to humans has never been a more poignant topic of research. Researchers in the virology department at the Faculty of Veterinary Medicine, Utrecht University, are busy finding out. Postdoctoral research fellow Daniel Hurdiss, together with principal investigator Raoul de Groot, and Utrecht Molecular Immunology Hub (UMI Hub) scientists Frank van Kuppeveld and Joost Snijder, have taken up the challenge of understanding how coronavirus proteins have adapted and evolved to elicit their survival within the human host.
In their recent pre-print publication, ‘Cryo-EM structure of coronavirus-HKU1 hemagglutinin esterase reveals architectural changes arising from prolonged circulation in humans,’ the researchers investigate coronavirus HKU1, a member of the Embecovirus subgenus, which seems particularly apt at crossing species barriers. The research reveals structural changes that have occurred in the hemagglutinin-esterase (HE) protein of HKU1 during the process of adaptation to its human host. The study shows that the lectin domain of HE has suffered several deletions and, in addition, has gained glycosylation sites, both of which are likely to facilitate immune evasion.
This study has achieved a surmountable task in solving the smallest viral glycoprotein structure by cryo-EM and is one of the very few <100 kDa proteins solved by this technique to date. The HE proteins of current, and possibly future, Embecoviruses could be a viable target for antiviral and vaccine development. It should be noted that this does not apply to SARS-CoV-2. Daniel hopes “this work will inspire researchers to study challenging viral proteins with cryo-EM to further our understanding of important human pathogens.”
Not surprisingly, Utrecht Molecular Immunology Hub scientists and coronavirus experts, Berend-Jan Bosch and Raoul de Groot have been inundated with questions and interviews related to the recent outbreak of the coronavirus. The virology department at the faculty of Veterinary Medicine aims to identify antibodies that can neutralize the novel coronavirus, which may aid development of vaccines and other antiviral strategies.
They will work together with their international partners to help develop a vaccine. "This is not something you can develop alone," explains Raoul de Groot. "We are not in competition with others to be the first to develop a vaccine. We will work together and share our knowledge as well as new developments about this virus as quickly as possible, so that researchers worldwide can put it to use immediately."
Berend-Jan Bosch explained that the development of a candidate vaccine takes around ten to twenty weeks: “That is not so long, but the test phase that follows, takes a lot of time. Safety and effectiveness must be tested."
It is comforting to know that when an outbreak like this occurs, scientists such as Raoul de Groot and Berend Jan Bosch, as well as scientists around the world, are doing their utmost to ensure the health and safety of the global population. More on this article can be found here
Grants Awarded to UMI Hub members - 2020
How can we use antibodies to fight bacteria? Suzan Rooijakkers, professor of microbiology at UMC Utrecht, has received a grant of € 2 million from the European Research Council (ERC) to answer this question. How is she going to do this? Read more here.
A consortium led by Geert-Jan Boons was one of three Technology Area (TA) projects, to receive funding for a project which will link allergenic proteins to complex sugars to open new avenues for preventing and treating food allergies. Technology Area is one of the public-private partnerships within the Science PPP fund. TA is designed to stimulate public-private partnership between at least two companies and two knowledge institutions. Geert -Jan Boons will lead a consortium of Utrecht University, University Medical Center Utrecht, Danone Nutricia Research, EnzyTag B.V. Find out more here.
The ENW Science PPP Board has successfully awarded funding to two molecular immunology research consortiums. One such consortium involves the successful application of professor dr. Martine Smit from the Vrije Universiteit Amsterdam, together with Utrecht University, Amsterdam University Medical Centers and two Dutch biotechnology companies QVQ and Argenx. Funding to the value of €830k for the Technology Area project “Multimeric antibody formats targeting GPCR networks in leukemic cells” will see the emloyment of a PhD student based at Utrecht University under the supervision of Utrecht Molecular Immunology (UMI) Hub member and grant applicant, assistant professor Dr. Wei Wu. The project involving chronic lymphocytic leukemia - uncontroled growth of specific white blood cells – will invesigate he generation of targeted antibodies for the treatment of this most common form of blood cancer.
Funding to the value of €292k for the Launchpad for Innovative Future Technology project “Sequencing of Serum Antibodies by Next Generation Mass Spectrometry Fragmentation Technologies” has been awarded to Albert Heck, professor of bio molecular mass spectrometry and coordinator of the Utrecht Molecular Immunology Hub,together with Utrecht University’s grant applicant Dr. Jean-Francois Greisch. The project involves the Dutch mass spectrometry support company MSVision, American based biotechnology company Genentech and the German division of the global biopharmaceutical company Roche. Funding will see the emloyment of a postdoctoral fellow over the course of three years. The project will investigate the patient – specific antibodies involved in fighting disesae within our blood, developing new mass spectrometric methods to caharacterize serum antibodies using electrons, infrared and ultraviolet light.
Utrecht Life Science Newsletters
The ULS monthly newsletter alternates between a full newsletter and a shorter news-update.
The newsletters can be found via the links:
Issue Dec 2020 - UMI Hub researcher studies SARS-CoV2-antibodies in mothers milk. Read more here.
Issue Sept 2020 - UMI hub researchers studied how enteroviruses reshape the structure, composition and metabolism of host cells in humans. The group of enteroviruses contains many important pathogens for humans. Read more here.
Issue July 2020 - UMI HUb Introduction. Read more here.
UMI Hub Seminars
An impressive 70 posters from Utrecht Univeristy (UU) and the University Medical Centre Utrecht (UMCU), were presentated at the Science for Life Conference held in Jaarbeurs on Monday 25 November. These poster included representatives from the Utrecht Molecular Immunology Hub as well as the Utrecht - Advanced In Vitro Model Hub
Congratulations to Laura Demmers UMI who received a prize for her poster on 'Single Cell: Clonal Diversity in HLA Class I Peptide Ligand Presentation.'
Congratulations also to Nicholas Pearce, Faculty of Science, for his poster on 'Re-factoring the B-factor: enabling intuitive structural-disorder analysis' and Maaike de Vries, UMCU, for her poster 'Stem cells are the principal intestinal epithelial responders to bacterial antigens.'
The 23rd of January 2020 saw guest speaker Prof. Maarten Merkx, who leads the protein engineering research group operating at the interface of chemical and synthetic biology at University of Technology, Eindhoven give his presentation on "Antibody sensing and actuation."
Postdoctoral fellow Dani Heesterbeek, University Medial Centre Utrecht, presented a very insightful talk on the UMI Hub showcase project entitled "Visualizing antibody-mediated killing of E.coli by the Membrane Attack Complex"
Wednesday 20 November saw the third successful series of the UMI Hubs Molecular Immunology seminar series. Over fifty research scientists attended this seminar from Utrecht University’s Faculties of Science and Veterinary Medicine, University Medical Centre and Gadeta b.v. Utrecht.
Postdoctoral fellow, Domenico Fasci gave an informative and interesting update on his UMI Hub showcase project, identifying ligands for a tumor reactive γ9δ2 TCR clone (CL5) which is currently being used to engineer conventional T cells in the development of a novel cancer immunotherapy (clinical trial NTR6541). A successful and productive collaborative effort between the group of Jurgen Kuball in the UMCU and the mass spectrometry groups of Wei Wu and Albert Heck.
Leo James from the MRC-LMB in Cambridge UK then presented his talk on “Trim-Away: Targeted degradation of pathogens and proteins by the cytosolic antibody receptor TRIM21” and informed us all that the biochemical and immunological textbooks need correction, as the assumption that antibodies are exclusively extracellular is incorrect. Trim 21 is in fact an intracellular antibody effector and is involved in an antibody mediated proteolysis pathway. This clever protein is ultimately responsible for the degradation of antibody bound pathogens and a Trim-Away method to develop novel therapeutics that can target disease-causing proteins for degradation is under investigation.
It was such an inspiring and informative presentation that question time continued long after Dr. James had finished his talk.
Felix Rey, Renowned professor and Laurate.Pasteur Institute, Paris. presented his talk on “Class II membrane fusion proteins in viruses and cells.” A very interesting UMI Hub seminar and well attended.
Berend Jan Bosch also presented the faculty of veterinary medicines, viral infections, and showcase project "Development of vaccination strategies that provide broad protection against antigenically variable pathogens.”.
The first UMI Hub seminar was attended by scientists from the University Medical Centre, Utrecht, as well as researchers from the faculties of Science and Veterinary medicine at Utrecht University. Prof Marek Basler Biozentrum, University of Basel and EMBO 2018 Gold Medal Award Winner gave a very insightful presentation
Prof. Suzan Rooijakkers (UMCU) presenting the showcase project "Structural insights into antibody-mediated bacterial killing" and outlined the research required in obtaining structural insights into antibody-mediated bacterial killing.