Researchers from the Canary Islands Health Service are participating in an international consortium that has discovered new immunological alterations that cause severe clinical Covid-19
According to the Ministry of Health, the studies carried out show that more than 13 percent of patients who develop critical Covid-19 (21 percent in those over 80 years of age) have "erroneous" antibodies that block the immune system itself and are responsible for approximately 20 percent of deaths from coronavirus. Likewise, at least another 1.8 percent of male patients under 60 years of age carry mutations in a gene located on the X chromosome (TLR7) that affects their immune response.
In both alterations, it is indicated that patients have a defect in immunity mediated by type I interferons, a group of 17 proteins crucial for protecting our cells against viral infections.
These discoveries, published in two articles in the journal Science Immunology, help explain why some individuals develop a severe infection by SARS-Cov-2. The findings also help to understand, at least in part, why mortality is higher in men than in women and allow for personalized treatments for patients with these alterations.
In September 2020, the international consortium COVID Human Genetic Effort (COVID HGE) published in the journal Science that at least 10 percent of individuals with critical Covid-19 (requiring admission to an ICU) have these abnormal autoantibodies, capable of neutralizing type I interferons, and that at least another 3.5 percent carry mutations in eight genes that affect their immune response, specifically immunity mediated by type I interferons. These findings were considered by Nature magazine as two of the ten most relevant scientific discoveries of 2020.
The studies now carried out by the consortium's researchers, expanding the number of individuals studied and using more sensitive techniques, show that autoantibodies against type I interferons are more frequent in patients with critical Covid-19 and are responsible for more than approximately 20 percent of deaths.
According to reports, these autoantibodies are found before the acquisition of the infection in 0.18 percent of individuals between 18 and 69 years of age, 1 percent of individuals between 70-79 years of age, and in more than 6 percent of those over 80. However, their frequency is considerably higher in some groups of patients with other immunological diseases.
On the other hand, another study confirms that mutations in the gene encoding the TLR7 protein produce a new primary immunodeficiency, which causes critical Covid-19 pneumonia in approximately 1.8 percent of men under 60 years of age. Similar results were observed when analyzing patients with severe pneumonia who did not require ICU admission. The TLR7 gene is located on the X chromosome, so it mainly affects males, who have a single X chromosome, unlike women who have two X chromosomes.
COVID HGE Consortium
The COVID HGE is an international consortium co-directed by Jean Laurent Casanova, from Rockefeller University in New York and a researcher at the Howard Hughes Medical Institute, and Helen Su, from the National Institute of Allergy and Infectious Diseases of the USA.
Around 50 centers participate in the consortium, and hundreds of hospitals around the world have also collaborated to obtain patient samples. One of the 50 centers is the Canary Islands Health Service, coordinated by Carlos Rodríguez-Gallego, from the Immunology service of the Dr. Negrín University Hospital of Gran Canaria and a member of the consortium's organizing committee. Carlos Flores, from the Research Unit of the Nuestra Señora de Candelaria University Hospital and the Technological and Renewable Energy Institute of Tenerife, and Rebeca Pérez de Diego, from the La Paz University Hospital Research Institute, also collaborate. Researchers from the Vall d'Hebron Hospital, IDIBELL, and the Spanish National Research Council of Barcelona have also participated in the study.
The results obtained allow the identification of people at risk of suffering a severe infection by the SARS-CoV-2 virus and open the way to adapt treatments to patients based on the genetic or molecular defect detected, an example of personalized and precision medicine, according to Carlos Rodríguez-Gallego.
The role of genetic predisposition
As the Ministry of Health recalls, infection by the SARS-CoV-2 virus causes an asymptomatic or mild infection in a large part of individuals. However, there are patients, even young ones, who develop very severe forms of the disease.
"It is known that age is associated with severe Covid-19 and that it occurs 1.5 times more frequently in men than in women. Several chronic diseases have been identified that predispose to severe infection, but their effect is relatively minor and does not explain many of the cases, especially in previously healthy individuals under 60 years of age," it is indicated.
In recent years, research in the field of primary immunodeficiencies has shown that unusual susceptibility to certain severe or recurrent infections "is due in many patients to genetic mutations that affect the immune response (the defenses)," explain Carlos Rodríguez-Gallego and Rebeca Pérez de Diego, researchers in the field of immunodeficiencies.
The researchers argue that this knowledge precisely led, at the beginning of the pandemic, to the creation of the COVID HGE consortium by researchers in the field of immunodeficiencies. The objective was to identify genetic and immunological alterations that would explain why some individuals develop the most severe forms of COVID-19. In a 2020 study, the researchers found that mutations in eight genes that govern immunity mediated by type I interferons were the cause of critical COVID-19 in approximately 3.5 percent of individuals, especially in those under 60 years of age.
For the current study, the consortium recruited patient samples from around the world, both severe and critical, as well as asymptomatic or mild, to study whether there might be some genetic basis that would explain the differences in severity produced by SARS-Cov-2 between men and women.
The researchers analyzed 1,202 samples from male patients, between 0.5 and 99 years of age, hospitalized with severe pneumonia who required admission to an ICU. Samples from 331 men, between 1.3 and 102 years of age, who had an asymptomatic or mild infection, and 262 men with severe but not critical pneumonia were also analyzed. Mutations in the genes located on the X chromosome were studied and it was found that mutations in the TLR7 gene were greatly increased. Subsequent immunological studies showed that many of these mutations caused a deficiency of the TLR7 protein that led to a greater susceptibility to infection by the virus.
According to reports, the TLR7 protein is a receptor found in a type of cell called plasmacytoid dendritic cells (pDC). TLR7 recognizes nucleic acids from the virus and triggers the production of type I interferons. pDCs and type I interferons are part of innate immunity, the components of the immune system that act immediately to combat and stop the infection, before acquired or adaptive immunity begins to develop its effector defense mechanisms, including the production of antibodies. Specifically, these interferons, in addition to activating other cells of the immune system, induce in the cells of our body the expression of hundreds of proteins involved in preventing the replication of the virus in our cells. The researchers explain that these patients could benefit from treatments with type I interferons, specifically IFN-α or IFN-β, already used in routine clinical practice in other diseases.
An autoimmune disorder
The existence of autoantibodies against various cytokines, molecules involved in communication between cells of the defense system, was already known. Some of them cause severe infections by mycobacteria or chronic mucocutaneous candidiasis. The existence of autoantibodies against type I interferons has been known since the 1980s.
However, no studies had been conducted that associated them with a predisposition to severe viral infection. These antibodies are a consequence of alterations in the tolerance mechanisms of our immune system, which are intended to prevent the development of immune responses (including the production of antibodies) against components of the body itself.
For the current study of autoantibodies against type I interferons, samples from 3,595 patients with critical Covid-19 (1,124 deaths), 522 patients with severe non-critical Covid-19, and 34,159 uninfected individuals were studied. The presence of these autoantibodies and the ability of the patients' serum to neutralize type I interferons in vitro were analyzed.
Carlos Rodríguez-Gallego explains that, in the case of an infection by the SARS-CoV-2 virus, these autoantibodies, by neutralizing type I interferons (mainly IFN-α and IFN-ω and, to a lesser extent, IFN-β), prevent the immediate immune response against the infection from being triggered. The findings show that these autoantibodies are present before the infection, that they are more frequent in men, and that the probability that they are present increases with age.
There are also some immunological diseases in which these autoantibodies are frequent. "These patients should be prioritized in vaccination plans and, in case of infection by SARS-CoV-2, specific treatments with interferons, or aimed at eliminating these autoantibodies, should be considered," it is noted.
Likewise, the findings raise the possibility that these autoantibodies may be involved in other severe viral infections, particularly in pandemics by other viruses such as the flu virus.
