Sunday, September 27, 2020

Research involving Canarian scientists discovers genetic causes of severe COVID-19

Image by Pete Linforth from Pixabay

Two articles are published in the prestigious international journal Science, with the participation of professionals from the Dr. Negrín University Hospital of Gran Canaria and the Hospital de La Candelaria, in Tenerife.

More than 10 percent of patients who develop severe COVID-19, some of them young and previously healthy, have "wrong" antibodies that attack the immune system itself, and at least another 3.5% are carriers of genetic mutations that affect to the immune response. In both groups, the result is basically the same: the patients present a defect in immunity mediated by type I interferons, a group of 17 proteins crucial for the protection of our cells against viral infections.

This is one of the main conclusions of two articles published in the prestigious international journal Science, with the participation of professionals from the Hospital Universitario de Gran Canaria Dr. Negrín and the Research Unit of the Hospital Universitario Nuestra Señora de Candelaria, Tenerife. attached to the Ministry of Health of the Government of the Canary Islands.

These findings help explain why some individuals develop an infection with SARS-CoV-2, the virus that causes COVID-19, much more severe than others of the same age (including, for example, individuals between 20 and 30 years previously who require admission to Intensive Care Units). These findings also help to understand for the first time the molecular bases that would explain the reason why mortality is higher in men than in women.

These results are the first obtained by researchers from the international COVID Human Genetic Effort consortium, a project co-directed by Jean Laurent Casanova, from Rockefeller University in New York and a Howard Hughes Medical Institute investigator, and Helen Su, from the Institute of Allergy and Infectious Diseases of the USA, in which around 50 Sequencing Centers participate.

These 50 centers include the Canarian Health Service, coordinated by Carlos Rodríguez Gallego (head of the Immunology service at the Dr. Negrín University Hospital of Gran Canaria), in collaboration with Carlos Flores (Research Unit of the Hospital Nuestra Señora de Candelaria and the Technological and Renewable Energies Institute of the Tenerife Island Council) and Rebeca Pérez de Diego (La Paz University Hospital Research Institute). In addition, hundreds of researchers from many countries have participated in the collection of samples and clinical data, including the Dr. Negrín University Hospital of Gran Canaria, the Maternal-Infant-Insular Hospital Complex of Las Palmas de Gran Canaria, and the Health Center de Schamann and the Guanarteme Health Center, both located in Las Palmas de Gran Canaria.

"The results obtained will probably have repercussions on the management and treatment of patients with these alterations, since they allow the identification of people at risk of suffering a serious infection and open the way to adapt treatments to patients based on the genetic or molecular defect detected, an example of personalized and precision medicine ”, explains Carlos Rodríguez-Gallego, coordinator of the Spanish Registry of Primary Immunodeficiencies.

Risk factors

Since the beginning of the pandemic it has been an enigma why the virus can cause an even asymptomatic infection in some individuals, while in others it causes a serious, even fatal, infection within a few days. It is known that age, sex and the existence of some previous pathologies or immunosuppression are risk factors for severe COVID-19. However, there are young, previously healthy individuals who develop a serious infection.

"The study of the complete exome with massive sequencing techniques has made it possible to greatly speed up the identification of the genetic causes that explain the severity of these patients, hence it is increasingly considered as a diagnostic aid in many medical fields," he explains. Carlos Flores.

In fact, "in recent years, research in the field of immunodeficiencies has shown that unusual susceptibility to certain infections is due to genetic mutations that affect the immune response", comment Carlos Rodríguez-Gallego and Rebeca Pérez de Diego . Some previous studies, carried out by Carlos Rodríguez-Gallego, collaborating with Canarian researchers and doctors, have allowed the identification of some of these innate errors of immunity in Canarian patients.

Collection of samples

In order to identify these genetic defects in patients with severe COVID-19, the consortium collected samples from patients around the world to study whether there could be any genetic basis that could explain the differences in severity produced by the SARS-CoV-2 virus. In a first study, researchers analyzed more than 650 samples from patients hospitalized with severe pneumonia who required admission to the ICU (14% of whom had died) and samples from 530 individuals who had an asymptomatic or mild infection were also analyzed.

In this study, 13 genes that are known to be critical for defense against influenza virus and govern immunity mediated by type I interferons were analyzed in both groups of patients. Type I interferons are part of innate immunity and intrinsic, the components of the immune system that act immediately to fight and stop infection before acquired or adaptive immunity begins to develop its defense effector mechanisms, such as the production of antibodies, which take several days to develop. Type I interferons are molecules from the group of cytokines produced by various types of cells, especially cells of the immune system, within a few hours after a viral infection. Secreted interferons are recognized by receptors found in practically all cell types in our body and trigger a powerful activity against the virus.

Vulnerability to the virus

After the genetic studies carried out in the Sequencing Centers, it soon began to be seen that there were critically ill patients who had rare variants in these 13 genes and more than 3% of critically ill patients had mutations that profoundly affected some of the genes studied. Subsequent experiments showed that the immune cells of these patients did not produce type I interferons in response to SARS-CoV-2. Studies carried out at Rockefeller University also showed that human cells carrying these mutations were more vulnerable to the virus and died in greater numbers and more rapidly than cells without these mutations. Some of these patients could benefit from treatment with type I interferons, currently used in some viral infections.

At least three types of infectious diseases are known which, in addition to being caused by mutations that affect certain proteins involved in immunity against these microorganisms, can also be the consequence of the existence of antibodies produced "erroneously" (auto-antibodies) versus those proteins. The consortium also studied whether a similar scenario could occur that predisposes to infection by SARS-CoV-2.

Study of 987 patients

987 patients with severe SARS-CoV-2 pneumonia were studied and it was found that more than 10% of the patients had autoantibodies that bound and neutralized the activity of type I interferons. In some cases, these autoantibodies were found already present in patient sera obtained before the patients were infected by SARS-CoV-2; in other patients, these autoantibodies were detected in samples obtained at the beginning of the infection, before, in case of being triggered by the virus, the immune system could develop the production of these antibodies. However, these autoantibodies were not detected in 663 individuals with mild or asymptomatic SARS-CoV-2 infection. When analyzing samples from 1,227 healthy individuals, obtained before the COVID-19 pandemic, four individuals (one in 300) had these autoantibodies.

"The data obtained indicate that these autoantibodies are the cause of the serious infection and not a consequence of the infection," explains Carlos Rodríguez-Gallego. "The fact that the majority of patients with severe COVID-19 with these autoantibodies are male (95%) indicates that their production could be related to sex," says Carlos Flores. "Patients with these autoantibodies could benefit from treatments aimed at their elimination or from treatments with type I interferons against which the patient does not have autoantibodies", explains Carlos Rodríguez-Gallego. The consortium continues to investigate other genetic variations that help identify and explain the variability in severity of SARS-CoV-2 infection.