Research seeks to understand why there are centenary elderly people who do not even have symptoms while young people die from Covid- OVALE

Research seeks to understand why there are centenary elderly people who do not even have symptoms while young people die from Covid- OVALE
Research seeks to understand why there are centenary elderly people who do not even have symptoms while young people die from Covid- OVALE

O Globo Agency | @journalovale

Parouhi Darakjian Kouyoumdjian had dengue and Covid-19 simultaneously, but showed symptoms more consistent with a mild form of the former. And he recovered well. Even more rare than Mrs. Parouhi’s name was her surprising case of co-infection, especially if it is taken into account that she has a century to live.

She fell ill last August, but her case continues to interest scientists. They search their cells and genes for clues to fight the pandemic. Ms. Parouhi, from São José do Rio Preto (SP), is among the centenarians studied by the University of São Paulo (USP) to identify why some apparently fragile people are infected and do not even develop symptoms, and others, young and strong, die Covid-19, with no known risk factors and even if they have access to good care.

It is at these extremes of the pandemic that science seeks to discover the weaknesses of the coronavirus. Sars-Cov-2 is a mass killer, but leaves exposed flanks, visible more easily in cases of resistance or extreme susceptibility.

The research, led by geneticist Mayana Zatz, coordinator of the Center for Human Genome and Stem Cell Studies at USP, investigates genes that can make people more resistant or vulnerable to the coronavirus.

The study is ongoing, but based on epidemiological data recently presented, Zatz is convinced that resistant people are more frequent than those susceptible to aggravation.

The problem is that, even so, there are millions who are vulnerable and so far there is no way to identify them. Nor is it easy to find the resistant because there is no way of knowing who was or was not exposed, due to low testing in Brazil.

– Centenarians with positive PCR are clearly resistant, as well as young people without comorbidities who have died. That is why we studied them – says Zatz.

Genetic and immunological characteristics influence how a person reacts to infections in general. This is known in the case of AIDS and hemorrhagic dengue, for example. Cases of HIV resistance are associated with a specific mutation in the CCR5 gene, which blocks the virus.

But Covid-19 appears to be even more complex, stresses Zatz. Not just one, but a set of genes would explain the fact that centenarians, some with comorbidities, in addition to their advanced age, escaped the coronavirus unharmed. Nor would the vulnerability be associated with a single gene.

Identifying these characteristics promises to reveal fundamental mechanisms of Covid-19 and ways to combat it, paving the way for the development of new vaccines and drugs. It also has more immediate applications:

– We want to understand, for example, the response to the vaccine. Why some people produce more antibodies than others, for example – he explains.

In addition to centenarians surviving and young people who died, the research investigates more than 80 nonagenarians who were cured or even manifested Covid-19 symptoms even though they were positive; 100 of the so-called discordant couples, defined as those in which one spouse became seriously ill or died and the other had nothing; and twins equally exposed to the coronavirus.

The study with young people who died of the disease without any comorbidity, with 45 individuals so far, is carried out in partnership with the group of Paulo Saldiva, full professor at the Department of Pathology, Faculty of Medicine, University of São Paulo (USP) .

Centenarians look fragile, but they are the toughest group. They can take any challenge from the environment, says Zatz. Her group studies 13 centenarians. The goal is, in addition to sequencing their genome, multiplying their cells in the laboratory, obtaining stem cells and studying their response to Sars-CoV-2, including variants.

Mrs. Parouhi was one of the first participants. She was born in what is now Armenia, but she arrived in Brazil at the age of 6, fleeing the massacre of Armenians by the Turks. Her youngest son, doctor João Aris Kouyoumdjian, 67, says that the mother went hungry and suffered many difficulties, but always had iron health.

– She continues very well, she has only some natural vision and hearing problems from aging. You have already taken both doses of the vaccine. Nothing scares her, but she is looking forward to the end of the pandemic – says Kouyoumdjian.

His mother has already made a special contribution to fighting the pandemic by giving her skin samples to extract cells. Another of the centenarians in the study is a 106-year-old woman who survived the Spanish flu (1918/19) and Covid-19 in 2020.

There is also a 104-year-old woman who does not have a kidney and that is not why Covid-19 got worse. Even more astonishing is a 114 year old woman from Paraíba. She died last year from causes unrelated to the pandemic and was one of the oldest people in the world. In fact, according to Zatz, he was the oldest person to survive Covid-19.

– This lady is an amazing case. Normally, cells taken from the skin for laboratory cultivation will die if they are not frozen within a few hours. It took hers five days to reach São Paulo and not only did they not die, but they were exceptionally active – says Zatz.

In a second stage of the work, Zatz plans to see how the resistant respond to the vaccine.

– They may have a different answer. Do they make more antibodies even with a single dose? This needs to be investigated – she stresses.

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To test this possibility, the USP group seeks to establish a partnership with the Butantan Institute, which produces CoronaVac.

Zatz is excited that the cases of resistant women are more frequent than they thought. She says she had no trouble finding so-called discordant couples.

– No one is more exposed to the virus than the spouse or partner of someone infected. Therefore, it is relevant that a person becomes ill or dies and his partner has nothing. We have already been contacted by more than a thousand people from all over the country in this situation and the e-mails of those interested in participating in the study continue to arrive – she highlights.

The geneticist recalls the case of a 72-year-old man, who became seriously ill, but whose 98-year-old wife and mother, who lives with the couple, had nothing.

Almost always, the healthy spouse of a seriously ill person does not even have antibodies. Of the 100 couples analyzed, only 5% of spouses who did not become ill had antibodies. And two-thirds of the spouses who did not fall ill are women.

Impossible to forget children

In young people who worsen terribly and die of Covid-19, even without known comorbidities, scientists speculate that there may be a deficient immune response controlled by a genetic configuration unfavorable to defense against the coronavirus.

The work of the team formed by Paulo Saldiva, with Marisa Dolhnikoff and Renata Monteiro, is a pioneer in non-invasive autopsies of victims of Covid-19. They look to the dead for information that will save lives.

– It’s never easy. Impossible to get used to autopsies of children. Our group is the one that most published studies with covid autopsies in the world, more than 110 autopsies. It is a kind of tragic and necessary study – he stresses.

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Among the initial group of 45 autopsied young victims of Covid-19 were four pregnant women, two babies of mothers with Covid-19, six children under the age of 12. The studies are ongoing, but Saldiva adds that the genetic sequencing of two of these children has already revealed that not only did they not have any disease other than Covid-19, they also did not have any known genetic variation associated with the vulnerability.

– We see so many people get sick because when the coronavirus circulates the most it ends up meeting people who have unfavorable polymorphisms. We resumed the autopsies and we are doing a sort of mapping of Covid-19, it apparently has its own brands – says Saldiva.

Needle in the haystack

Zatz adds that studies in the United States have indicated that there are at least three genes – all of them from the immune system – that may be associated with greater vulnerability. The resistance can be even more complex. There are clues that the so-called HLA system is involved, says Zatz.

The HLA system is crucial in defenses. It is he who identifies and reacts to invaders, such as viruses. But hunting for changes in HLA is like looking for a needle in a haystack. Its genes, six major and more than 100 related, are on chromosome 6, and there are more than 22,548 alleles (ways a gene can appear) known. Mutations in these genes are associated with a number of autoimmune diseases, such as lupus and type 1 diabetes.

– This is a long-term study that can help us fight this and the next pandemic – emphasizes Zatz.

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