Joining the dots to tackle COVID-19: a bioinformatics approach
The global COVID-19 pandemic is a huge challenge for healthcare and science alike. Part of that is understanding how the SARS-Cov-2 virus causes such severe disease in some patients, triggering what is known as a cytokine storm that sends the immune system into overdrive.
The global COVID-19 pandemic is a huge challenge for healthcare and science alike. Part of that is understanding how the SARS-Cov-2 virus causes such severe disease in some patients, triggering what is known as a cytokine storm that sends the immune system into overdrive. Dr Tamas Korcsmaros and his team at Earlham Institute and Quadram Institute are applying their expertise in systems biology to help join the dots and paint a holistic picture of how COVID-19 affects the human body.
Stay at home, protect the NHS, save lives. Wash your hands for 20 seconds and avoid touching your face. Keep two metres apart at all times. While the public health advice to combat COVID-19 has been undeniably simple, the virus itself remains an enigma.
The global death toll is well in excess of 250,000, with some patients fighting for their lives in intensive care units, yet others seemingly shrug it off with no symptoms to suggest they were ever infected.
Since the SARS-CoV-2 virus began spreading rapidly around the world, scientists have been racing to understand its pathogenicity. Global collaborations and open data sharing have yielded vast amounts of data which the bioscience community is using to find a potential treatment to reduce the mortality associated with COVID-19.
The mounting evidence points to a peculiar feature of SARS-CoV-2. Far from being limited to the respiratory tract, its deadly effects have been shown to act all over the body - from the lungs to the gut and the kidneys - even causing strokes in otherwise healthy, younger patients.
One particularly dangerous effect, which occurs in some patients between 7 and 10 days after infection, is a cytokine storm. The virus essentially causes the immune system to go into overdrive. Struggling to cope, the body can fill the lungs with fluid, cause multiple organ failure, and perhaps even lead to some neurological effect.
If we are to stand any chance of developing effective treatments - and managing this pandemic - we have to find out what is driving the response of our body to SARS-CoV-2.
A systems-based bioinformatics approach
Dr Tamas Korcsmaros and his group are perfectly positioned in this regard, with over ten years’ experience in developing bioinformatics tools and techniques to understand the complex nature of inflammatory bowel disease (IBD) via the multitude of interactions that occur within and between cells occupying the human gut. This approach allows scientists to look at systems as a whole, rather than their individual parts.
The reams of data collected by the international scientific community detail the genomes and mutations of SARS-CoV-2 variants across different locations; the structure of the viral proteins; their host targets in human cells; the transcriptomics changes in infected cells; cell or tissue-level differences in the blood or in the body of COVID-19 patients; and human genomic information from patients.
“At present, these data are not connected,” explains Dr Korcsmaros. “Using our demonstrated integrative approaches, we can combine them to produce a more holistic understanding of the effect of SARS-CoV-2, point out non-trivial connections, and facilitate the search for relevant therapeutic options.”
Dr Korcsmaros and his group at Earlham Institute and Quadram Institute are joining with Dr Julio Saez-Rodriguez of the University of Heidelberg as part of the international COVID-19 Disease Map effort.
“Our main goal is to understand the systemic effect of SARS-Cov-2 on our body,” says Dr Korcsmaros. “In particular, why in certain patients the viral infection leads to a much more severe, inflammatory phenotype that causes life-threatening over-activation of our own immune system.
“To achieve this, primarily, we are going to create computational models and then we will test some of the predictions in-house or with expert collaborators.”
Our main goal is to understand the systemic effect of SARS-Cov-2 on our body.
Systems biology comes to the fore
To draw an interesting parallel, an article published recently by the NPC stated that “Covid-19 means systems thinking is no longer optional.” This was directed at human civilization from a broad perspective, but the lessons apply equally to biology - as indeed they should. To quote the piece, “Systems thinking goes beyond individual actions to connections, causes and consequences.”
This is precisely the attitude Dr Korcsmaros applies in his work on systems approaches to understanding gut health. Active projects tackle the highly infectious and deadly Salmonella, as well as chronic illness, such as Inflammatory Bowel Disease. His group has developed a range of machine learning and bioinformatics tools that help scientists approach these areas using multi-omics and network-based methods.
SalmoNet, for example, is a resource which links information on how genes and metabolic pathways are regulated in Salmonella, and how proteins interact with each other, looking at all of the interactions within and between multiple strains of the bacterium. PhD student Marton Olbei, who works on the platform, explained in a blog that for SalmoNet “understanding and discovering new biological mechanisms or potential therapeutic intervention targets is one of the most compelling uses.”
SignaLink is another resource which allows users to explore signalling pathways and their cross-talk, including transcription factors, regulatory components and enzymes through an onion-like, multi-layered structure. It’s similar to SalmoNet, but this resource is for humans and model systems such as zebrafish and the nematode worm C. elegans. Other network resources developed by the Korcsmaros Group include NavigOmix and the Autophagy Regulatory Network.
Systems thinking goes beyond individual actions to connections, causes and consequences.
Joining the dots of COVID-19
One resource developed by Korcsmaros and Saez-Rodriguez that will be used directly in the effort to understand COVID-19 is OmniPath. This signalling pathway resource will help researchers understand some of the genetic changes that take place in patients after infection by the virus, honing down to single infected cells.
PhD student Agatha Treveil and postdoctoral scientists Dr Paddy Sudhakar and Dr Dezső Módos have already carried out a successful pilot study to understand the effect of the virus on infected lung cells. The next stage is to link signalling in primary infected cells to those cells involved in the cytokine storm - the aim being to find ways to limit the dangerous immune responses seen later on in some infections.
The second part of the three-pronged approach aims to disentangle the root causes of the cytokine storm by tracing the trajectory of infection from overactive immune cells back to the origin of infection.
The team of PhD student Marton Olbei, and senior postdoctoral scientist Dr Isabelle Hautefort is further detailing the interactions between cytokines and immune cells in response to COVID-19, to see where communication in an over-active immune system can be altered.
Communication between blood cell types (pink boxes) and organs (blue boxes) facilitated by cytokines (coloured arrows) elevated following a SARS-CoV-2 infection.
The cytokine storm effect is not unique to COVID-19 but occurs in response to a number of similar infections. The team is also, therefore, comparing the data from the current pandemic to that from others such as the coronaviruses SARS and MERS, as well as H5N1 and H7N9 influenza.
In this way, through identifying specific immune responses involved in the cytokine storm - and perhaps shared pathways - it may well be possible to identify therapeutic targets.
Differences in elevated cytokine (white circle) responses in patients following an infection (coloured boxes). Models like this can show us the differences in how patients can react to different viruses, leading to a better understanding of the pathogenesis.
The hunt for an effective treatment
The third and final research objective is to combine the results of the first two strands to identify potential pre-existing therapeutic approaches for the treatment of COVID-19. By comparing drug and cytokine profiles from third-party coronavirus datasets, and using our systems-level knowledge base, the group will evaluate potential candidates suggested in recent papers and rank them based on cell type or mechanism of action.
The group is working together with two world-leading experts of this field, the cheminformatics group of Dr Andreas Bender at the University of Cambridge and Dr Julio Saez-Rodriguez and his group in Heidelberg.
With the search for an effective treatment for COVID-19 still ongoing, the work of the Korcsmaros Group and others around the world is vital.
“These analyses can potentially help find pathways and cell types that can be pharmaceutically targeted, thereby speeding up the process of finding treatment options for infected patients - especially those at high risk,” says Dr Korcsmaros.
“With our work developing new pipelines, resources and integrated analysis, we also hope to support the work of our collaborators and the wider research community, who are doing their utmost to help during this time of crisis.”