Researchers in Brazil discover a gene that may provide protection against COVID-19

Scientists at the University of São Paulo analysed blood samples donated by six serodiscordant couples – the situation one partner becomes infected but the other does not – where female partners were resistant to SARS-CoV-2 despite intense contact with their infected male partners

During the COVID-19 pandemic, health worker Maria Tereza Malheiros Sapienza’s curiosity was aroused by her seeming immunity to SARS-CoV-2 – the virus that causes COVID-19. Maria’s husband, Marcelo Sapienza was a doctor who was twice infected – in April 2020 and January 2022 – but she remained well and asymptomatic even though she was in direct contact with him prior to bouts of illness.

The Sapienzas (pictured) took part in a study on serodiscordant couples conducted by the Human Genome and Stem Cell Research Center (HUG-CELL) at the University of São Paulo (USP) and funded FAPESP – a public, taxpayer-funded, grant providing research foundation in the State of São Paulo, Brazil.

Serodiscordant couples are so called because one partner is infected and the other remains asymptomatic although both are exposed to the virus and do not use any kind of special protection or adopt other behaviours to avoid infection.

Genetic material from 86 couples was analysed in the study. Only six remained serodiscordant throughout the pandemic and in all six cases the male partner was reinfected – this was confirmed by PCR – testing while the female partner remained uninfected or asymptomatic.

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The blood samples analysed from these couples showed that the women who were immune to the virus exhibited elevated expression of the gene IFIT3 –interferon-inducible protein with tetrapeptide repeats 3 – when compared with their male partners. Expression of the gene in symptomatic infected women was in line with that of the men.

“This gene is part of the antiviral response. It has been described in previous studies as being related to protection against other viral diseases, such as dengue, hepatitis B and adenovirus.

“In our study, however, we succeeded in demonstrating this protection for the first time beyond theory, as it’s highly improbable that all six women weren’t exposed to SARS-CoV-2 [given that they were living in] conditions that included sharing bedrooms and caring for infected husbands,” said Mateus Vidigal, first author of the article. The study was his postdoctoral project and was supported by FAPESP. 

The gene IFIT3 encodes a protein with the same name that binds to the virus’s RNA, inhibiting its replication and preventing infection by blocking cell invasion.

“The virus invades one or two cells, but the process of replication, breaking out through the cell membrane and invading the largest possible number of other cells, is interrupted very early on.

“The protein IFIT3 ‘sticks’ to the viral RNA, preventing its replication. It’s not that these women weren’t infected, they were, but the virus hardly multiplied at all inside their cells and so they didn’t develop the disease,” Vidigal explained.

The study of serodiscordant couples began in 2020 during the COVID-19 pandemic. In the first stage, the researchers analysed the exome – the protein-encoding portion of the genome – of 86 couples, finding a difference in two genes between resistant and infected partners. These variations apparently led to the production of molecules that inhibited activation of natural killer (NK) cells only in the infected partners. NK cells are lymphocytes of the innate immune system that control tumours and microbial infections. 

During the pandemic, several cases of reinfection occurred in the group of volunteers recruited for the study, and only six women remained resistant. To investigate protective mechanisms, the researchers analysed blood samples from these couples on two occasions:

• In 2020, shortly after the men’s first infection.
• In 2022, after their second infection.

It is worth noting that on the second occasion, the participants had already received two doses of a COVID-19 vaccine.

“In our analysis of these samples, we isolated the mononuclear cells in the peripheral blood, mainly lymphocytes and monocytes, and stimulated them in the lab with a synthetic viral agent that mimics SARS-CoV-2.

“This experiment showed that the cells from resistant women overexpressed IFIT3 compared with both their male partners and a [control] group of five women who did develop COVID-19 disease,” Vidigal said.

The study produced other important findings, such as the possibility that IFIT3 could be a novel target for therapies aimed at strengthening the innate immune response to a range of viruses – the protection afforded by overexpression of this gene does not just form part of the response to SARS-CoV-2.

“The key result of this research is undoubtedly the discovery of a biomarker of resistance to the virus. The design of the study enables us to be almost certain that women were exposed to the virus and exhibited resistance.

“We also reproduced in the lab what may have happened in their cells when they came into contact with SARS-CoV-2,” said Edecio Cunha Neto, co-author of the article, and a professor at the University of São Paulo’s Medical School.

“We now need to extend our knowledge of the biology of resistance, finding out more about the mechanisms that lead to overexpression of IFIT3, for example. So, beyond this important discovery, yet more questions raised by our study remain to be answered,” he said.

For further reading please visit: 10.3389/fcimb.2024.1464581