Feature • Perspectives • Slide
The secret to combatting coronavirus – is it in your genes?
Nazifa Tabassum, Research Assistant, BioTED
& Dr Muhammad Sougatul Islam, Director, BioTED
The pandemic ofCOVID-19 has brought scientists of various disciplines from all over the globe under an umbrella and they are working in unison towards understanding it. A strange nature of the virusis how selective it is; with cases illustrating how not all infected people develop the symptoms. However, it has also been put into light that alongside the older generation and those with underlying health complications, some perfectly healthy and young individuals have also shown up to be one of those among the severe cases. This provides scientists with a new piece of the puzzle – could looking into the patients’ DNA help us understand why some individuals develop serious illness whereas others don’t? Identifying this could pave the way for new treatments and help protect the most
Ongoing genetic projects are already collecting the DNA of thousands of participants for analysis, with samples from places like Italy, where the situation is dire. Scientists hope to achieve an analytical comparison of the DNA of previously perfectly healthy individuals who developed a serious infection of COVID-19 with individuals who got infected but only showed mild or no symptoms of the disease. Andrea Ganna, a geneticist at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) have commented on how this could explain if a vast difference in clinical outcomes among different countries is actually due to genetic variation, which is a very open-ended argument with the data available right now.
Some researchers admit to how the outcome of these gene hunts could be unpredictable. However, there are some suspected candidates, including the gene coding for the cell surface protein angiotensin-converting enzyme 2 (ACE2), which is used by the coronavirus to enter the host’s airway cells.
Variations in this ACE2 gene could lead to an altered version of the receptor being present in different individuals, meaning for some individuals the virus is able to enter the cells easily, whereas for others it is more difficult. This is agreed by immunologist Philip Murphy of the National Institute of Allergy and Infectious Diseases (NIAID), whose lab had previously found something similar with another human cell surface protein, CCR5, which makes some individuals highly resistant to HIV.
FIMM’s Andrea Ganna is currently leading a project to collect the genetic information of COVID-19 patients from all around the world. This recent idea was formulated into a project which is now called the COVID-19 Host Genetics Initiative. Their affiliations now include other large biobank studies which follow thousands of volunteers annually to test for a relationship between their DNA and health. Situated mostly in Europe and the United States, more than a dozen biobanks have expressed their interest in sharing COVID-19 data from volunteers who had willingly agreed.
Among these biobanks is FinnGen, which comprise of genetic information of up to 5% of the Finnish population. The UK biobank, being one of the world’s largest with over 500,000 participants, have also expressed their plans for addition of COVID-19 health data from its participants. Other companies include the Icelandic company deCODE Genetics, which contains the health data and genome of more than 364,000 inhabitants. Harvard University’s Personal Genome Project is also in on this project, with its database having access to information regarding its participants’ full genome, tissue samples and health data. Questionnaires had been sent to thousands of its participants earlier this month to ask about their COVID-19 states, with more than 600 participants based in the United States responding within 48 hours. The University’s research team commented on how this goes to show that most people want to do whatever they can to help understand this crisis.
On the other side, are researches combining forces with hospitals directly for genetic information. Alessandra Renieri of Italy’s University of Siena stated that over 11 of the nation’s hospitals could be expected to give ethics approval for her team’s collection of DNA samples from patients.
Renieri has also mentioned howgenetic differences could prove to be a key factor for some individuals being more susceptible to severe acute pneumonia.
Rockefeller University’s pediatrics researcher Jean-Laurent Casanova, specializing in identification of rare genes that could potentially lead to healthy young individuals being susceptible to specific serious illnesses, is trying to form a network of pediatricians worldwide. This team effort would aim to study the relatively few young individuals who had developed enough of a serious case of COVID-19 to have gotten admitted to intensive care. This study would be limited to severe cases from patients who were previously healthy and also under 50 years of age, which is the cohortfor whoma genetic factor is the probable cause.
Alongside genetic variants of the ACE2 receptors, scientists are also looking at differences between other genes such as the human leukocyte antigen gene. This gene can influence the immune system’s response to viruses and bacteria, which in turns dictates how severe the disease becomes in the individual. Some investigators requested to follow up on a finding by a Chinese team which reported that individuals with type O blood could be protected by the virus. These findings would be delved into further by individuals such as Stanford University’s human geneticist Manuel Rivas, who is also contributing to the COVID-19 Host Genetics Initiative.
This initiative is expected to take off as more genetic information is collected from the exponentially increasing number of COVID19 positive individuals. The lead of the COVID-19 Host Genetics Initiativeis expecting their first detection of genes which make some individuals develop more severe cases of the virus than others, to take place sometime within the next couple of months.
Another area of genetics that my shed light on COVID-19 complications is “cytokine storm”. A cytokine storm is an overproduction of immune cells and their activating compounds—cytokines—which, in something like a flu infection, is often associated with a surge of activated immune cells into the lungs. The resulting lung inflammation and fluid buildup can lead to respiratory distress and can be contaminated by a secondary bacterial pneumonia. This increases the risk of mortality in patients.
It’s not the most widely-understood phenomenon, but it occurs in several types of infections and autoimmune conditions. It appears to be particularly relevant in outbreaks of new flu variants. Cytokine storm is now seen as a likely major cause of mortality in the 1918-20 “Spanish flu”–which killed more than 50 million people worldwide and the H1N1 “swine flu” and H5N1 “bird flu” of recent years—and now COVID-19. In these pandemics, sometimes patients at higher risk to die were often relatively young adults with seemingly strong immune reactions to the infection. Recently in a lives discussion we talked to a scientist, Dr Mouhammed Uddin Dafil from Sick Kids Hospital, Toronto in Canada in live discussion with BioTED. He mentioned that they are carrying out a study on human genome interaction with viral genome and trying to find out the heterogeneity in terms immune response and other abnormalities. They looking at HLA genes for example who play a critical role in immune reaction and variation in those genes might pay role in severity of immune reactions.
Is there Recent Data on Cytokine Storms?
A recent pre-print study reviews the role of cytokines in SARS-CoV-2 infection.
Not all patients with COVID-19 develop the same symptoms, but the immunological determinants of a poor prognosis are unknown. In this pre-print article, Yang, Y et al. followed a cohort of 53 clinically moderate and severe patients; they conducted a multiplex screen for 48 cytokines and correlated these results with lab tests, clinical characteristics and viral loads. They found a marked increase of 14 cytokines in patients with COVID-19 compared with healthy controls.
* Many elevated cytokines with COVID-19 onset compared to healthy controls (IFNy, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-18, HGF, MCP-3, MIG, M-CSF, G-CSF, MIG-1a, and IP-10).
* IP-10, IL-1Ra, and MCP-3 (esp. together) were associated with disease severity and fatal outcome.
* IP-10 was correlated to patient viral load (r=0.3006, p=0.0075).
* IP-10, IL-1Ra, and MCP-3 were correlated to loss of lung function (PaO2/FaO2 (arterial/atmospheric O2) and Murray Score (lung injury) with MCP-3 being the most correlated (r=0.4104 p<0.0001 and r=0.5107 p<0.0001 respectively).
* Viral load (Lower Ct Value from qRT-PCR) was associated with upregulated IP-10 only (not IL-1Ra or MCP-3) and was mildly correlated with decreased lung function: PaO2/FaO2 (arterial/atmospheric O2) and Murray Score (lung injury).
* Lymphopenia (decreased CD4 and CD8 T cells) and increased neutrophil correlated w/ severe patients.
* Complications were associated with COVID severity (ARDS, hepatic insufficiency, renal insufficiency).
At this point of pandemic we can apparently say that studies are ongoing and we have to wait some more time until the role of human genome in complications caused by COVID-19 are revealed. Science behind it might help to find some possible interventions to deal with COVID-19 patients in near future.