An Interview with Dr. Antonio Salas Ellacuriaga, Faculty of Medicine Professor – University of Santiago de Compostela, and Health Research Institute (Instituto de Investigación Sanitaria – IDIS) Spain
“Our mission is to advance knowledge of the genetic basis of infections with special focus on the pediatrics, and to contribute to the development of individualized strategies for their prevention and treatment.”
Understanding the underlying host genetic differences and individual responses to the SARS-CoV-2 virus is key to deciphering the disease susceptibility, severity, and outcomes. Host genome variation will help elucidate why some individuals with underlying conditions or genetic predispositions may have higher or lower risk. It may also provide better pharmaceutical solutions based on genetics.
According to the World Health Organization, COVID-19, the disease caused by the SARS-CoV-2 virus, originated in China in December 2019 and within a few months affected over 200 countries, contributing to over 470,000 deaths, and infecting over 9M people (June, 2020) with the figures increasing daily.
Along with ongoing testing efforts, government funded initiatives, health systems, and academia are collecting and banking samples from consented individuals. Biobanked samples will be paramount in the days ahead to quickly and accurately stratify populations and begin to understand severity and susceptibility. Meta-analyses, a type of statistical analysis that combines multiple, independent studies together to address a specific question, is being used to understand the characteristics of SARS-CoV-2 infections.
A handful of researchers globally quickly identified the potential deleterious effects of the novel coronavirus and went to work. One such research team is Professor Dr. Antonio Salas, a Faculty of Medicine at the University of Santiago de Compostela (USC), Spain, his colleague Professor Dr. Federico Martinón-Torres, the Head of Pediatrics at the Hospital Clínico Universitario de Santiago de Compostela, and their talented group of scientists. They launched a concerted research effort to understand SARS-CoV-2 end of January 2020 just weeks after news of the virus began circulating in scientific communities. This collaborative team was well-positioned to take on SARS-CoV-2 infection research, given their 14+ years of research of human populations with special focus on infectious disease, vaccines and pediatrics.
We spoke with Professor Salas on their SARS-CoV-2 infection research efforts around the genomics of the host and susceptibility to the infection.
Thermo Fisher Scientific: What is your perspective on underlying human genetics and SARS-CoV-2 infection susceptibility, severity & outcomes? How does this differ by age – young versus old?
Professor Salas: SARS-CoV-2 infection presents different phenotypes, from asymptomatic cases to severe pneumonia and multi-organ failure leading to death. The genetic variability of the host may play a main role in regulating the susceptibility and the severity of the disease, as it has been shown previously in other infectious diseases, that is, explaining the different behavior of the same microorganism in different subjects. The experience of our group in host genomics and transcriptomics in infectious diseases leads us to hypothesize that the human host genetics may explain the differential patterns of SARS-CoV-2 infection in different subjects and age groups.
In a very narrow collaborative effort with my colleague Prof. Martinón, we have been working for several years on infectomics in children, and the host is key to any infectious disease, and SARS-CoV-2 infections won’t be an exception. The behavior of SARS-CoV-2 in children may pose the key clues to solve the problem. Apparently, the attack rate is not different to that in adults (15%), but children have a milder course than adults – using words of my colleague Prof. Martinón, indeed the host could have the answer!
Thermo Fisher Scientific: What is your perspective on the role of arrays in host genetics and SARS-CoV-2 infection research?
Professor Salas: During the last decade we have been using many different technologies to explore genome variation, including parallel sequencing (NGS) and arrays. In a research setting, the arrays may allow quick and deep searching of susceptibility factors in the host. With adequate subject selection, it may be possible to get answers in a rapid and efficient manner. The acquired knowledge can also allow us to quickly move on to the next phase of translational research. If SARS-CoV-2 is selecting specific hosts, only host genetic analysis will tell us the answer.
Thermo Fisher Scientific: What is the role of meta-analysis in SARS-CoV-2 infection research?
Professor Salas: I have no doubt that meta-analysis will play an important role. There are many initiatives worldwide targeting the genome of infected samples with different phenotypes. Our group is carrying out infectomics, including not only genomics, but transcriptomics, epigenomics, and proteomics, and other experiments focused on gene editing using CRISPR. We are also integrated in several international consortia on infectious diseases as well as other mega-consortia specifically set up in this coronavirus era (e.g. https://www.covid19hg.org).
Therefore, we are in a good position to claim that meta-analysis will play a role in the near future of SARS-CoV-2 infection research.
Thermo Fisher Scientific: What are the challenges in meta-analysis and how are they overcome?
Professor Salas: There is a main issue that worries me – the same samples are being genotyped or sequenced in different reports. Fortunately, for those exclusively interested in genomics, there are many ways to detect duplicates when exploring the genome variation directly. However, meta-analyses, including case series and opinion reports, do not use genome data directly, and this might be a real challenge in future comparisons. This problem is not exclusive to SARS-CoV-2 infections, but it is much more notable now because hundreds of groups worldwide – many with no previous research activity on infectious diseases – have now devoted their efforts to SARS-CoV-2 infection research.
Meta-analyses are very powerful tools for summarizing knowledge on SARS-CoV-2 infections, and this shed further light not only on susceptibility to the disease, but also to identify variants important for drug development research. There are different kinds of meta-analyses and the challenges depending on the main focus e.g. confirm a previous discovery versus discovery GWAS meta-analysis.
The use of common technologies and SNP arrays would facilitate comparisons and reduce problematic technological problems. There are other issues in meta-analysis that are very well-known for those carrying out meta-analyses, such as the need to control for population stratification due to e.g. different ancestral backgrounds of subjects, other confounding factors, phenotyping etc.
Thermo Fisher Scientific: Why are you interested in the Applied BiosystemsTM AxiomTM Human Genotyping SARS-CoV-2 Research Array? What is the value of a SARS-CoV-2 specific module in an array?
Professor Salas: We put our best in the selection of the genes according to our experience and the existing knowledge and, at the same time, based on robust scientific evidence.
The current module includes more than 7,300 genes with special focus on ones specific for SARS-CoV-2 infection research. This list includes genes related to immunological pathways to all the different phenotypes that have been presented in our research including respiratory infection (acute respiratory distress syndrome phenotype), anosmia-ageusia (loss of smell, loss of taste) involved genes and the most recent Kawasaki-like or shock-like phenotype described in children. This array is a tool that can be used to quickly advance the understanding of SARS-CoV-2 infections.
Furthermore, to the best of our knowledge, this is by far the most convenient array available to target host genomics. In our opinion, when using a more general array you run the risk of losing the focus and there is not scientific reason for using an array where most of the genes were selected based on the etiopathology of other diseases that have little to do with SARS-CoV-2 infections. Moreover, there is a lack of statistical power if you type SNPs that are not of specific interest to infectious disease and run the risk for false positive inflation. This reasoning applies in fact to previous products available in the market, because none of them were specifically designed for targeting infectious diseases.
Thermo Fisher Scientific: What are the other content markers of importance in SARS-CoV-2 infection research?
Professor Salas: Content markers that are of particular importance include obvious candidates, such as ACE2 (angiotensin-converting enzyme-2) or other genes related to immunology, HLA (human leukocyte antigen), CFH (complement factor H gene), etc. Additionally, we have included genes representing key pathways to SARS-CoV-2 infection, including inflammation (septic shock, macrophage activity, cytokines, mucosal immunity, etc.), severe respiratory infection, hypertension, neurological process (anosmia, ageusia, etc.), coagulation (hypercoagulability, pulmonary embolisms, etc.), diabetes and insulin resistance, rheumatoid arthritis, Kawasaki vasculitis, etc.
SNP selection was coordinated with geneticists and bioinformaticians from Thermo Fisher Scientific. Thereby, SNPs were selected taking into account a large set of markers for genome-wide imputation coverage (GWAS grid) down to 1% MAF, and adding markers for imputation as required to maximize coverage in the genes selected (still down to 1% MAF) and direct tiling on the array of nonsynonymous coding markers, mostly quite rare, of specific interest. So far this is mostly for genes predicted to interact directly with viral proteins, e.g. SNPs predicted to affect the ACE2/Spike protein interface, etc.
Also included are some markers of the Axiom Precision Medicine Diversity Research Array modules such as pharmacogenomics and blood typing, and eQTLs for relevant genes.
Thermo Fisher Scientific: Can you tell us more about your team, collaborative efforts, and research focus areas?
Professor Salas: There are two laboratories that fall under myself and my colleague, Prof. Dr. Federico Martinón-Torres. My laboratory is GenPoB (http://genpob.eu) and the focus is on basic science. Prof. Dr. Martinón-Torres’ lab is GenViP (http://genvip.eu) and has a main focus on clinical and translational research. Both belong and are physically located together at the Health Research Institute of Santiago de Compostela in the Hospital Clínico Universitario de Santiago de Compostela. We have extensive collaborative experience in large-scale multicenter studies related to infectious diseases and “omics”. We coordinate several international clinical consortia and have been involved with 8 EU-funded projects1. The group shares collaborative research lines in “-omics” and infectious diseases with Imperial College of London, PENTA Fondazione, Genomic Institute of Singapore, Rabdoud University, Oxford Gene Technology, ReSVinet, Sistemas Genómicos, and Nationwide Children’s Hospital of Ohio, among others.
Our conversation concluded with Professor Salas thanking the young and multidisciplinary team of GenPoB and Genvip, cutting-edge tools and competitive funding opportunities. The collective teams aim to lead on the forefront of international infectious disease research. The group is committed to continuing collaborating with a range of research groups worldwide to become an important player in understanding SARS-CoV-2 and more broadly the battle against infectious diseases.
1.PERFORM (GA 668303), PoC-ID (GA 634415), PREPARE (GA 602525), EUCLIDS (GA 279185), ZIKACTION (GA 734857), RESCEU (GA 116019), C4C (GA 777389) and DIAMONDS (GA 848196).