Couples help researchers discover gene that may afford protection against COVID-19 microbiologystudy

During the COVID-19 pandemic, health worker Maria Tereza Malheiros Sapienza’s curiosity was aroused by her immunity to SARS-CoV-2: her husband, Marcelo Sapienza, a physician, was infected twice (in April 2020 and January 2022), but she remained perfectly well and asymptomatic even though she was in direct contact with him prior to both infections.

This curiosity led the Sapienzas to join a study on serodiscordant couples conducted by the Human Genome and Stem Cell Research Center (HUG-CELL) and hosted by the University of São Paulo (USP). Serodiscordant couples are so called because one spouse or partner is infected and the other remains asymptomatic although both are exposed to the virus and do not use any kind of special protection.

Genetic material from 86 couples, including the Sapienzas, was analyzed in the study. Only six remained serodiscordant throughout the pandemic, and in all six cases the male partner was reinfected (confirmed by PCR) while the female partner remained uninfected or asymptomatic.

The results of the study are reported in an article published in the journal Frontiers in Cellular and Infection Microbiology.

When the researchers analyzed blood samples from these couples, they discovered that the women who were immune to the virus exhibited elevated expression of the gene IFIT3 (interferon-inducible protein with tetrapeptide repeats 3) 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’s 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 under conditions that included sharing bedrooms and caring for infected husbands,” said Mateus Vidigal, first author of the article. The study was his postdoctoral project.

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.

Novel target

The study of serodiscordant couples began in 2020 when the pandemic reached Brazil. In the first stage, the researchers analyzed the exome (the protein-encoding portion of the genome) of 86 couples, finding a difference in two genes between resistant and infected partners. These variants 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 tumors 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 analyzed blood samples from these couples on two occasions: in 2020, shortly after the men’s first infection, and in 2022, after their second infection. It is worth noting that on this 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,” Vidigal said.

In addition to satisfying the Sapienzas’ curiosity, 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 is not only 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 totally 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, a co-author of the article, a professor at the University of São Paulo’s Medical School (FM-USP) and a researcher at its Heart Institute (INCOR).

“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.”