University of São Paulo: Immune system deficiencies explain part of the severe cases of covid-19

The international consortium COVID Human Genetic Effort , made up of more than 150 scientists, with the participation of researchers from the Institute of Biomedical Sciences (ICB) at USP, identified two genetic causes for the worsening of cases of covid-19. Published in the scientific journal Science Immunology in August, the studies show that autoantibodies ( antibodies directed to the body’s own cells and tissues) compromise the performance of the immune system and are responsible for about 14% of critical cases of covid-19 and almost 20% of all fatal cases. In addition, a genetic mutation found in 1.8% of men explains the presence of severe infection in some young people.

The first study highlights an error in the immune system that leads to the production of autoantibodies that neutralize and destroy type 1 interferons – glycoproteins with high antiviral activity that are important for fighting infections. “The organism starts to fight the virus and an antibody appears that ‘pulls the handbrake’ of its immune response. It’s like swimming against the current”, explains physician and researcher Antonio Condino-Neto, a member of the consortium and coordinator of the ICB’s Human Immunology Laboratory.

“The data indicate that some individuals, not just the elderly, may have genetic susceptibility to the disease. And they show why some people are tougher and others aren’t, regardless of age – although it’s common for the immune system to weaken with aging. The discovery strengthens our thesis that the problem of severe cases is not just the virus, but the individual’s immune system”, highlights the researcher.

This phenomenon was observed in 13.6% of patients with severe covid-19 and in 21% of patients over 80 years of age. These autoantibodies were also detected in 18% of the 1,124 patients who died. To reach these results, samples were collected from approximately 3,600 patients from hospitals around the world for gene sequencing.

“The data indicate that some individuals, not just the elderly, may have genetic susceptibility to the disease. And they show why some people are tougher and others aren’t, regardless of age – although it’s common for the immune system to weaken with aging. The discovery strengthens our thesis that the problem of severe cases is not just the virus, but the individual’s immune system”, highlights the researcher.

Gene mutation – The second study details the role of a mutation in the recessive TLR7 gene, linked to the X chromosome, which contributes to the development of severe covid-19. This gene regulates toll-like 7, an intracellular receptor that handles viral responses, recognizing patterns and activating mechanisms to attack the virus. With the mutation in the gene, the receptor does not act as expected against the coronavirus, which ends up causing a very serious infection.

Extremely rare, deficiency was identified in 1.8% of men under the age of 60 who had unexplained critical pneumonia due to covid-19 – including two boys aged between 7 and 12 years. For this, 1,102 male patients between six months and 99 years of age were analyzed.

Possible therapies
Scientists already have a treatment hypothesis to circumvent these susceptibilities. Next year, an international clinical trial will be carried out with interferon beta, a compound used to treat autoimmune diseases such as multiple sclerosis. It is a drug with long experience of use in the clinic, which would help speed up the tests until its approval. It is already known, for example, the dose regimen to apply it safely, as well as its possible adverse effects.

“We carried out in vitro tests and the drug worked to correct the problem pointed out in the first study, the autoantibodies. It works by activating the mechanisms of innate immunity, to stop the virus right from the start, replacing the interferons that the person’s immune system is trying to destroy”, says Condino-Neto. “Imagine that the immune system of these patients is a street full of holes and bumps: the drug would resurface their asphalt”, he adds.

In the case of mutations in the TLR7 gene, more research is needed to outline a therapeutic strategy. “One of our best hypotheses is interferon beta itself, because when the toll-like 7 receptor does not work, it cannot trigger the mechanisms of cytokine synthesis. So, this individual must be lacking interferon beta. But we still need to prove this”, details the professor.

Next steps
The group will also continue looking for new genes that impact the worsening of covid-19. At the ICB, researcher Condino-Neto and his team, consisting of doctoral student Lucila Barreto and post-doctor Letícia Gomes de Pontes, collect patient samples and generate genetic sequencing data, detailing not only the performance of autoantibodies but also the profiles of the proteins. “We will have data from around 120 Brazilian patients. When we finish generating and analyzing this information, we will be able to carry out meta-analysis studies, crossing them with other databases”, he says.

In addition to the ICB team, other Brazilian researchers also participate in the consortium, such as Carolina Prando, from Hospital Pequeno Príncipe in Curitiba, professor Mayana Zatz, from USP’s Biosciences Institute (IB), as well as collaborators from the Faculty of Medicine (FM) of USP.

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