Published in Nature: First insights into the Porcine Deltacoronavirus spike

Further to CARE’s SARS-CoV-2 research, CARE partner Utrecht University (UU) has studied the Porcine Deltacoronavirus (PDCoV) spike, providing crucial insights for developing antiviral strategies. PDCoV, an emerging enteric pathogen in pigs, has recently been detected in children with acute febrile illness. PDCoV enters cells by binding its spike (S) protein to the host receptor aminopeptidase N (APN) and can use the APN of different species, ranging from humans, felines to chickens, highlighting its capacity for interspecies transmission. Despite this zoonotic threat, the antigenic structure of PDCoV, i.e. the molecular structures on the surface of viruses that are recognized by the immune system and are capable of triggering immune responses, remains unknown.

UU and collaborators generated and characterized a set of human monoclonal antibodies (mAbs) targeting the S protein, which can effectively neutralize virus infection. Through an integrated approach involving functional and structural analyses, UU successfully pinpointed three vulnerable regions within the prefusion S trimer. The team showed that mAb binding to the spike S1A domain is important to shift the S1B domain towards an open conformation, which is necessary for binding to the APN receptor. Other antibodies targeting the S1B domain inhibited binding to the receptor, thereby preventing infection. The epitopes of these S1B-targeting antibodies were concealed in the prefusion S trimer conformation, suggestive of an intriguing immune evasion mechanism in PDCoV. One S1B mAb, broadly reactive against avian deltacoronaviruses, targeted a highly conserved epitope on S1B that entirely overlapped with APN-interacting residues.

The identification of neutralizing epitopes on the PDCoV S protein provides essential functional and structural insights for understanding humoral immune response against this zoonotic pathogen. These discoveries hold promise for developing potent tools for outbreak preparedness against prospective deltacoronaviruses in humans.

To learn more, click here: Neutralizing Antibodies Reveal Cryptic Vulnerabilities and Interdomain Crosstalk in the Porcine Deltacoronavirus Spike

CARE – Infographic – Work Package 5 – identifying immune markers contributing to the host immune responses to SARS-CoV-2 infection and their correlations with clinical and virological outcomes​

CARE has 8 Work Packages but do you know what each one does? Here, you can learn about the Work Package 5 team, their objectives, their partners, their breakthrough moments and more.

The infographic is also available here

CARE’s Young Researchers – Introducing Manon Laporte, PhD, KU Leuven

Read about how Manon’s work in phenotypic antiviral screening enabled the discovery of a novel target in the replication cycle of coronaviruses and a small molecule inhibitor that can address that target, plus how this approach may benefit future pandemic preparedness across many virus types.

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It comprises 38 partners, from both industry and academia, in a set-up of eight multidisciplinary work-packages (WPs). In this series, we highlight the work of some of the young researchers involved in CARE as part of their PhD or postdoctoral work. Here, we learn how this opportunity has benefited Manon, while simultaneously benefiting CARE and its ambition to help society defeat COVID-19 and future pandemics.

What experience did you have working on a Public Private Partnership before joining CARE? 

I had no experience working on a PPP before but many of my current colleagues did.

How did your involvement in CARE come about?

I joined the group of Johan Neyts (the academic lead of Work Package 1) two years ago, approximately one year after the start of CARE. At that point, I had two years’ experience working with SARS-CoV-2, both at the Rega Institute in Leuven with my former Principal Investigator, Lieve Naesens and during my postdoc at the Garcia-Sastre lab in New York at the Icahn School of Medicine at Mount Sinai. Given my experience with SARS-CoV-2, I started working on the CARE antiviral projects together with Dirk Jochmans, research manager of Johan Neyts’ group.

Tell us about the work you have been doing in the CARE consortium

I’m part of the team working on Work Package 1: “Anti-coronavirus drug discovery in phenotypic virus-cell-based assays.” I plan and oversee the in vitro antiviral testing for different partners within CARE. I also helped to establish antiviral assays for high throughput screening using our unique lab-in-a box system CAPS-IT (https://rega.kuleuven.be/cmt/capsit) and I have set up several mode-of-action assays to elucidate the working mechanism of newly identified hits.

Our biggest project within CARE is the coronavirus M assembly inhibitor project together with CD3 (https://www.cd3.be/) and CISTIM (https://www.cistim.be/). When I joined two years ago, we had two interesting compound series. I have been very closely involved in the optimization process and in solving the molecular mechanism of action of ‘series 8’. These compounds inhibit the virus via an entirely novel and hitherto unknown way, namely by blocking the viral membrane (M) protein, the key regulator of coronavirus assembly.

What highlights can you share from your time in the CARE consortium so far?

Scientifically I feel very fortunate to be able to work on the coronavirus assembly inhibitor story. We discovered a novel druggable target in the replication cycle of coronaviruses and a small molecule inhibitor that can address that target.

In science, you sometimes have to be a little lucky and it is an amazing opportunity to work on such an exciting story with a great group of people, both within our team at KU Leuven, the medicinal chemists at CD3 and CISTIM, and our collaborators at other institutes. Within CARE, especially with the team of Daniel Hurdiss (Utrecht University) and the team of Eric Snijder (Leiden University Medical Centre).

Why does this work matter?

We prove again that phenotypic antiviral screening is a successful way of identifying novel antiviral targets. Until today, effective antiviral therapies for many viruses with epidemic and pandemic potential are still lacking (e.g., paramyxo-, pneumo-, bunya-, flavi-, toga-, filo-, enteroviruses). The mission of our lab (www.antivirals.be) is to develop small-molecule antiviral drugs (or combinations thereof) against these viruses using phenotypic high-throughput screening as a starting point. Hits from these screening campaigns are further optimized and we try to unravel their mode of action which often leads to the discovery of novel antiviral targets, as was the case for the coronavirus M targeting compounds. Besides my work on SARS-CoV-2, I am currently focusing on a small molecule discovery project for henipaviruses. Nipah virus is a highly lethal paramyxovirus (case fatality rate is estimated at 40% to 75%) that causes almost yearly outbreaks and can be transmitted from human to human. There is no treatment or vaccine available and Nipah virus is on the WHO R&D blueprint list of priority diseases. It is our goal to discover novel small-molecule inhibitors with pan-henipa coverage so that, in the event of a big outbreak we don’t lag behind with antiviral therapy as was the case during the COVID-19 outbreak.

How have you benefited from your involvement in CARE?

I have benefited by expanding my network significantly. Thanks to CARE it is possible to work with other experts in the field in a very efficient way. The amount of data we can collect by working together is truly unique.

CARE – Infographic – Work Package 4 – Generation and characterisation of monoclonal antibodies against SARS-CoV-2 and related coronaviruses

CARE has 8 Work Packages but do you know what each one does? Here, you can learn about the Work Package 4 team, their objectives, their partners, their breakthrough moments and more.

The infographic is also available here

CARE’s Young Researchers – Introducing Holly Kerr, PhD, University of Edinburgh

Read about how Holly’s work in getting a better understanding of host response and resulting disease may help identify alternative or complementary approaches to direct-acting anti-virals by targeting the host.

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It comprises 38 partners, from both industry and academia, in a set-up of eight multidisciplinary work-packages (WPs). In this series, we highlight the work of some of the young researchers involved in CARE as part of their PhD or postdoctoral work. Here, we learn how this opportunity has benefited Holly, while simultaneously benefiting CARE and its ambition to help society defeat COVID-19 and future pandemics.

What experience did you have working on a Public Private Partnership before joining CARE? 

I had no experience of being in a consortium of this type within a research context. However, before starting my PhD in 2020, I was recruited as a Laboratory Scientist at one of the UK’s Lighthouse Laboratories that were responsible for the mass COVID-19 testing effort. These labs were only possible due to a huge collaboration between industry, academia, and government. Working at the Lighthouse Lab gave me my first insight into the importance, impact and challenges of this kind of partnership.

Why did you decide to get involved in CARE?

My PhD project within the Tait-Burkard lab aims to better understand the host factors involved in SARS-CoV-2 and other human coronavirus infections. This includes following up the results of an RNAi Druggable Genome screen which was conducted as part of the CARE work package 5 research. Starting my PhD during the pandemic and following the work in the Lighthouse Lab, I was motivated to align my research project with the pandemic response. I was inspired by the cross-disciplinary and well-supported team effort that IMI CARE champions and feel grateful to have this consortium as a network within my research.

How did your involvement in CARE come about?

I was encouraged in the planning of my PhD project by my supervisor, Christine Tait-Burkard, to be involved in CARE, given my interest in host factors, antivirals and pandemic preparedness.

Tell us about the work you have been doing in the CARE consortium

My role in the CARE consortium involves analysing and validating an in vitro RNAi host factor screen of SARS-CoV-2 as part of the aims of Work Package 5. I have generated hit lists of genes involved in SARS-CoV-2 infection from the screen, compared these to host factors identified in other published work, including results within our work package, and conducted pathway and network analysis of our hits. I’ve validated two clusters of hits from anti-viral and pro-viral pathways and begun to decipher their role in infection. Identified host factors in our screen are “druggable”, in that drugs exist that target them, or are they are predicted to be targeted with drugs based on their structure. To follow up the results of our screen, I have been testing the use of repurposed host-directed anti-viral therapies in SARS-CoV-2 infection in vitro and I am planning to take forward promising candidates to an in vivo study this summer.

What highlights can you share from your time in the CARE consortium so far?

The highlight from my time in CARE has been attending the annual meeting in March this year in Leiden. It was exciting to see my work presented and helpful to receive feedback from a global group of experts. I really enjoyed meeting researchers from across the consortium, learning about the development of multiple promising treatment options from across the other work packages and being a part of the strategic discussions for the future of the consortium as we prepare for the next pandemic. As an early career researcher, these conversations are not often made accessible to me – I appreciated the opportunity to have the insight into decision making processes at this level.

Why does this work matter?

This work matters because despite the vast amount of research conducted following the emergence of the third highly pathogenic human coronavirus in the past 20 years, we are arguably still some way from being prepared for the next pandemic. In particular, we are yet to find effective, broad-spectrum, “off-the-shelf” therapeutic options. Coronaviruses continue to burden human, animal and environmental health and there is a risk of further emerging strains. By understanding the host response, we can better understand the resulting disease and perhaps identify alternative or complementary approaches to direct-acting antivirals by targeting the host.

What are or were the biggest challenges you have experienced (and how did you overcome them?)

Challenges I have experienced include keeping up with the variants of concern that evolved in real-time during our research. This was overcome though collaboration with clinical scientists and teamwork within the Tait-Burkard lab.  We divided the labour to harness different skills from different scientists doing different tasks, including growing virus, testing stocks, sequencing, and then running relevant assays that tell us more about how the latest variants interact with the host within human cells.

How have you benefited from your involvement in CARE?

I have benefited by gaining insight into leading research in coronavirus biology, meeting experts from across Europe and putting my research in the context of other work under the same aim.

What advice would you give to someone getting involved in a Public Private Partnership? 

I would tell them to do it, grab the opportunities that arise and try to enjoy the feeling of being the least experienced person in the room – it means you have the most to learn!