Why does the individual response to SARS-CoV-2 virus infection vary so much from one person to another? A new work has identified that 10% of people who develop COVID-19 have antibodies that attack the immune system itself and prevent an adequate response against the virus. In addition, another 3.5% have mutations in genes that affect the immune response, increasing vulnerability to life-threatening COVID-19. The study, led by The Rockefeller University in New York and the Necker Hospital for Sick Children in Paris, had the participation of various services from the Vall d’Hebron University Hospital and research groups from Vall d’Hebron Institute of Research (VHIR) and the results are published in two papers in Science. From VHIR, it has been led by the research group on Infection in the Immunosuppressed Pediatric Patient and on Diagnostic Immunology.
The results of the research show that in 15% of cases there are genetic and immunological factors that can explain the appearance of severe forms of COVID-19. The patients that have been identified have in common a defect in the activity of type I interferons, molecules of the immune system that play a key role in fighting viral infections. These proteins can be blocked by auto-antibodies or, if there are certain mutations, they may not be produced in sufficient amounts. This can lead to an inadequate immune response against the virus and therefore a greater severity of the disease.
Genetic mutations that prevent the response against the virus
In the first study, researchers analyzed genetic variations from blood samples from more than 650 patients who had been hospitalized for life-threatening pneumonia due to COVID-19, 14% of whom had died. Samples from another group of over 530 people with asymptomatic or benign infection were also included. The researchers looked for differences between the two groups across 13 genes known to be critical for the body’s defense against the influenza virus using type I interferons.
The results showed that a significant number of people with severe disease carried rare variants in these 13 genes, and more than 3% of them had a mutation that prevented an adequate response against SARS-CoV-2 due to lack of activity of type I interferons. “Type I interferons are one of the main mechanisms that innate immunity has to fight against viral infections. In fact, during the last 15 years, mutations in these 13 genes have already been described in specific and exceptionally severe cases of other viral infections such as influenza or herpesvirus encephalitis. What has surprised us in this study is the high frequency of these alterations in patients with severe COVID-19”, explains Dr. Roger Colobran, researcher at the Diagnostic Immunology research group at VHIR.
An autoimmune response in more than 10% of severe cases
On the other hand, the second article describes an autoimmune response against type I interferons. In this case, the researchers examined 987 patients with life-threatening COVID-19 pneumonia and found that more than 10% had auto-antibodies against interferons at the onset of their infection. In some cases, these antibodies were detected in blood samples taken before patients became infected; in others, they were found in the early stages of the infection.
95 patients of the 101 with these antibodies against type I interferons were men. “This gender bias suggests the presence of some genetic factor (which could be located on the X chromosome) that somehow favors the higher prevalence of this autoimmune phenomenon in men. This is one of the hypotheses in which COVID Human Genetic Effort consortium is working on”, points out Dr. Colobran. In addition, about half of the patients who had these antibodies were older than 65 years old, while they were only found in 38% of those under 65 years old, which suggests that the frequency of these antibodies increase with age. Thus, the autoimmune response against interferons could explain the greater vulnerability of men and people over 65 years old to severe COVID-19.
The presence of auto-antibodies was also analyzed in healthy population. In these cases, only 4 of 1,227 people tested had this type of antibody. “These findings reinforce the idea that these auto-antibodies play a role in causing these serious forms and that they are not a consequence”, says Dr. Andrea Martín, researcher at the research group on Infection in Immunosuppressed Pediatric Patients.
Findings for a better care of patients at risk of severe COVID-19
The identification of genetic mutations and antibodies against type I interferons is important to implement medical interventions that allowed detecting people at risk of developing a severe form of COVID-19 and treating this group of patients in a more appropriate way. For example, if a person doesn’t have type I interferons, these molecules could be administered early in the infection to try to avoid developing severe forms of the disease. However, it is necessary to bear in mind that this may not be a feasible approach in an emergency medicine as in the case of COVID-19.
In contrast, in the case of a person with antibodies against type I interferons, their detection by ELISA techniques may be applicable to routine clinical practice. “If this finding is confirmed, doors are opened to the treatment of severe forms of COVID-19 such as plasmapheresis, the use of other types of interferons or the pharmacological elimination of plasma cells”, concludes Dr. Pere Soler-Palacín, head of the research group on Infection in Immunosuppressed Pediatric Patients.
COVID Human Genetic Effort: A Consortium for COVID-19 research
The COVID Human Genetic Effort (COVIDHGE) initiative is an international consortium led by the Rockefeller University of New York and the Necker Hospital for Sick Children in Paris that includes hundreds of hospitals around the world and participants of various nationalities from Asia, Europe, Latin America and the Middle East. Now, the consortium continues its research to find new genetic variants that may affect other aspects of the immune response in COVID-19. The findings related to auto-antibodies against type I interferons are currently being validated with more than 2,000 samples that are part of the COVID-19 collection at Vall d’Hebron Hospital Campus.
Vall d’Hebron is part, together with Bellvitge Biomedical Research Institute (IDIBELL), of one of the two sequencing hubs in Spain. The other one is located in the Canary Islands led by Servicio Canario de la Salud.
From Vall d’Hebron, the research group on Infection in the Immunosuppressed Pediatric Patient and Diagnostic Immunology groups at VHIR, in addition to the Clinical and Molecular Genetics Area and Biobank at the hospital, have participated in the study. At the State level, other hospitals and research centers are also part of the consortium such as IDIBELL, Hospital Universitario de Gran Canaria Doctor Negrín, Fundación Mútua de Terrassa, IrsiCaixa, Universitat de Vic, iCREA, Institut d'Investigacions Biomèdiques de Barcelona-CSIC, Hospital del Mar, Hospital de Bellvitge, Complejo Hospitalario de Navarra, Clínica Universitaria de Navarra, Hospital Universitario Infanta Leonor, Hospital Universitario de Burgos and Centre Nacional d’Anàlisi Genòmica (CNAG).
