21 December 2020

Session three of the Progress Educational Trust (PET) annual conference explored the genetic and genomic links to susceptibility to severe COVID-19. Sarah Norcross, director at PET, opened the session with the unfortunate news that one of the speakers Dr Kri Stefnsson was unable to participate in the session due to illness.

The session was chaired by Dr Roger Highfield, science director at the Science Museum Group mild-mannered and a clear speaker, he chaired the session with ease. Dr Highfield introduced the first speaker Dr Sharon Moalem a scientist and physician who specialises in genetics. Dr Moalem is a bestselling author, with titles including: 'How Sex Works', 'Inheritance: How Our Genes Change Our Lives and Our Lives Change Our Genes', and 'The Better Half: On the Genetic Superiority of Women' (see BioNews 1050).

Dr Moalem focused his talk on the law of homogameity, and whether COVID-19 illustrates the genetic/genomic resiliency of women. He began by briefing the audience on the basics of mammalian genetics, how we have 46 chromosomes, one pair of which is sex chromosomes, containing either XX for a female, termed homogametic, or XY for a male, termed heterogametic. A system has arisen in females, where in each cell one X chromosomes is 'turned off', called X-inactivation or silencing. However, it has now been discovered that X-inactivation is not complete, and that about 25 percent of the second X chromosome is still active. Dr Moalem explained that this allows females to have more 'genetic horse power' within each of her cells.

X-linked conditions, such as fragile X, red-green colour blindness and Duchene muscular dystrophy, are more common in males, as men do not have another X chromosome. Females do not simply have a 'back up X', but in some cases their non-faulty gene produces and shares the required protein, essentially rescuing the cells containing the faulty gene, which would have died. In other cases, cells with such a mutation do not survive, but cell lines with the healthy X proliferate to compensate. This leads to tissues with an uneven distribution of active Xs, called X-skewing.

Moving onto COVID-19, why is the mortality rate for males higher than that for females? Dr Moalem proposed the law of homogameity, which predicts that the homogametic sex has a survival advantage across the life course. Females have a greater genetic diversity due to having an extra X-chromosome, which equates to 1000 more genes. The X chromosome contains many immune-related genes eg, TLR7 which is used by certain cells in the body to detect for single-stranded RNA viruses, like SARS-CoV-2, the virus which leads to COVID-19. As females have two variations of TLR7 they have two different immune cell populations to help detect the virus. However, there is a cost to homogameity increased autoimmunity, with 'long COVID' proving to be four times more common in women.

In the USA there is currently no requirement for drug approval from the FDA to use both male and female cells. Scientists can use just one sex, yet females' cells work in a corporative way. Dr Moalem believes there should be a completely separate drug approval process as many drugs behave differently in men and women.

Dr Highfield returned to introduce the second speaker Dr Qian Zhang a research associate at the St Giles Laboratory of Human Genetics of Infectious Diseases, at Rockefeller University in New York City. Dr Zhang's research specialises in inborn errors of immunity (IEIs) inherited disorders that impair normal immune development and function.

Dr Zhang focused her talk on type I interferon immunity in patients with life-threatening COVID-19 and began by explaining how early on in the pandemic it became clear that people infected with SARS-CoV-2 responded differently. Most were asymptomatic and developed either no or very mild clinical symptoms. A small proportion of patients developed life-threatening disease. This phenomenon is seen in all infectious diseases from bacteria, fungi and viruses.

Dr Zhang and her research team studied whether the same genetic mutations already known to be associated with life-threatening influenza infections also increase the risk of life-threatening COVID-19 pneumonia. There are three genes, TLR3, IRF7 and IRF9, in the type I interferon pathway that are mutated in people who develop life-threatening influenza. In addition, ten further genes, IFNAR1, IFNAR2, STAT1, STAT2, IRF3, UNC93B, TRIF, NEMO, TRAF3 and TBK1, are reported to affect severity of other viral infections.

Type I interferon is a cytokine and has 17 different subtypes, which lead to the stimulation of several hundred interferon-stimulated genes that have an antiviral function. Hence, if this pathway is disrupted by a genetic mutation, viruses are able to gain a foothold more easily.

Dr Zhang's team sequenced the whole of the genome of over 600 severe COVID-19 patients to determine whether they had mutations in any of these 13 genes and discovered over 118 variants, of which, 24 resulted in loss of function.

Four patients with autosomal recessive mutations causing a complete loss of function in IRF7 and IFNAR1had never been hospitalised before contracting COVID-19, much to Dr Zhang's surprise. IRF7 is a transcription factor that amplifies the antiviral signal of type I interferon, and IFNAR1 is one of two proteins that make the receptor for type I interferons. Patients with these mutations are unable to mount an interferon response to COVID-19 infection.

Dr Zhang reassuringly explained that these mutations are rare, less than one in 1000 in the population, as such they cannot explain why there are so many people dying of COVID-19. This led Dr Zhang to the second part of her research: studying whether auto-antibodies against type I interferons lead to the same phenotype as these rare mutations.

Over ten percent of patients with life-threatening COVID-19 make auto-antibodies against two of the type I interferons. These neutralising auto-antibodies can entirely block the protective effect of type I interferons, which may be the cause of severe COVID-19.

Surprisingly, 95 percent of patients with these auto-antibodies were male and only six were female. One of these female patients had incontinentia pigmenti (IP), which is caused by a NEMO mutation on the X chromosome, leading to skewed X-inactivation a perfect example of the genetic diseases Dr Moalem was discussing earlier in the session. Even though such patients have two X chromosomes, most of the tissues in their bodies express just one X chromosome, and so these females are more similar to males in terms of susceptibility.

Combining both parts of her research, Dr Zhang's team discovered that selected patients with TLR3 and IRF7 mutations could simply be treated with type I interferon. However, this treatment did not work for patients with IFNAR1 mutations because the receptor is absent, but treatment with wildtype IFNAR1 was successful. Unfortunately, neither treatment worked for patients with auto-antibodies.

In her opinion COVID-19 could be considered an X-linked disease, even though the candidate on the X-chromosome has yet to be discovered and furthermore, type I interferon immunity is essential to control COVID-19 infection.

Dr Highfield returned to update the audience on Dr Stefnsson's research, investigating the genetic code of each COVID-19 infection in Iceland, giving an insight into the origins, and how the infection was caught, spread and mutated. Surprisingly, a large number of cases came from the UK. Similar research in the UK has detected 1356 independent introductions of the virus, mostly due to inbound international travel a third came from Spain, over a quarter from France and 14 percent from Italy.

The session provoked interesting discussions within the Q&As, with the first asking Dr Moalem whether females are less severely affected by other viruses, which he concluded as true, particularly for influenza. But even for HIV-1, women are much better at clearing the virus and have a much lower viral load.

With a personal interest, I took the opportunity to ask Dr Zhang whether patients with type I interferon IEIs were more susceptible to severe COVID-19, as such a disease affects members of my own family. Dr Zhang confirmed that such patients are more likely to suffer with severe COVID-19 and had now tested 20 IP patients discovering at least a quarter had high levels of autoantibodies to type I interferons. She warned that these females should be very cautious and shield as much as possible, as any patient with auto-antibodies is very difficult to treat. Reassuringly, patients with certain genetic mutations that do not have high levels of autoantibodies to type I interferon can simply be treated early with interferon injections.

I will leave with a final comment from Dr Moalem: 'Men are more biologically fragile when compared to women.' Whoever said that women were the weaker sex?

PET would like to thank the sponsor of this session, the Anne McLaren Memorial Trust Fund, and the other sponsors of its conference - the Edwards and Steptoe Research Trust Fund, ESHRE, Wellcome, the European Sperm Bank, Ferring Pharmaceuticals, the London Women's Clinic, Merck, Theramex, Vitrolife and the Institute of Medical Ethics.

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Correlation and Causation: What Can Genetics and Genomics Tell Us about COVID-19? - BioNews