Genetic, immunological abnormalities in Type I interferon pathway are risk factors for severe COVID-19

Newswise — Bethesda, Md – Individuals with severe forms of COVID-19 disease can present with compromised type I interferon (IFN) responses based on their genetics, according to results published in two papers today in the journal Science.  Type I IFN responses are critical for protecting cells and the body from more severe disease after acute viral infection.

In "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19" and "Autoantibodies against type I IFNs in patients with life-threatening COVID-19," scientists participating in the international COVID Human Genetics Effort, including a team from the Uniformed Services University of the Health Sciences, report that more than 10 percent of patients who develop severe COVID-19 have antibodies that attack type I IFN itself instead of the virus. In addition, more than 3.5 percent carry specific genetic mutations that decrease the production of type I IFNs or induce an inadequate type I IFN response. These findings help to explain why some people with no underlying conditions develop a disease much more severe than others in their age group, and may also provide a molecular explanation for why more men die from the disease than women.

The COVID Human Genetic Effort is a global consortium that includes more than 50 sequencing hubs, including The American Genome Center (TAGC) at USU, and hundreds of hospitals and investigators around the world. CHGE is co-led by Dr. Helen Su, a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and Dr. Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University.  USU researchers, Dr. Clifton Dalgard, director of TAGC and Associate Professor of Anatomy, Physiology and Genetics, and Dr. Andrew Snow, Associate Professor of Pharmacology and Molecular Therapeutics, are both among the international team of scientists affiliated with CHGE working to study genetic influences of COVID-19 disease by sequencing the genomes of patients infected with SARS-CoV-2, the virus that causes COVID-19.  The pair have partnered closely with Dr. Su and her team to forge a strong collaboration with additional investigators at NIAID.

In the Science studies, Dalgard’s team at TAGC sequenced samples from hundreds of COVID-19 patients from around the world, focusing mostly on patients from clinical centers in Brescia and Monza, Italy, that faced the first significant wave of COVID-19 in Europe, and who were recruited through a collaboration with Dr. Luigi D. Notarangelo, chief of the Laboratory of Clinical Immunology and Microbiology at NIAID. These centers provided samples to NIAID, which were then transferred to TAGC for rapid whole genome sequencing to study genetic influences of disease severity. TAGC also acquired and sequenced samples from additional European and U.S.-based patients in several states.

The first Science article describes genetic abnormalities in patients with severe forms of COVID-19 at the level of 13 genes already known to govern the immune response controlled by type I IFNs against the influenza virus. Mutations in these genes are the cause of some severe forms of influenza and other viral infections. Surprisingly, these genetic variants are also present in adults who have not been particularly ill before, especially with the flu. Regardless of their age, people with these mutations are at greater risk of developing a potentially fatal form of influenza or COVID-19. Administration of type I IFN early in these patients could be a therapeutic avenue, without noticeable side effects if taken for a short time.

In addition to Dalgard and Snow, Miranda Tompkins and Camille Alba, Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF) contract employees at TAGC, along with HJF contract employee Christopher Luthers and graduate student Bradly Bauman in Dr. Snow’s lab, and Daniel Hupalo, John Rosenberger, Gauthaman Sukumar, Matthew Wilkerson, and Xijun Zhang, all HJF contract employees in TAGC/PRIMER, also participated in the research as part of the "NIAID-USUHS/TAGC COVID Immunity Group" and are co-authors on the paper.

In the second study, the researchers show in patients with severe forms of COVID-19, the presence of high levels of antibodies in the blood directed against type I IFNs (“autoantibodies”) are capable of neutralizing the effect of these important anti-viral molecules. Remarkably, these autoantibodies are found in more than 10% of patients developing severe pneumonia from SARS-CoV2 infection. In contrast, type I IFN autoantibodies were absent in people who develop a mild form of the disease and are extremely rare in the general population. Production of these autoantibodies is likely indicative of other genetic alterations that are currently being investigated. Their presence prevents type I IFNs from working against the SARS-CoV-2 virus, particularly in men. Such patients may benefit from plasmapheresis (removal of the liquid part of the blood containing in particular white blood cells and antibodies), or other treatments that may reduce the production of these antibodies by B lymphocytes, although further investigation is needed to confirm this. Moreover, these results suggest that it may be necessary to screen the general population in order to detect these autoantibodies as one potential prognostic indicator of severe COVID-19.

Dalgard and Snow are among the co-authors within the "NIAID-USUHS Immune Response to COVID Group" cited in the second paper. 

“I am so honored and excited to work with Dr. Dalgard at TAGC and our incredible collaborators at NIAID on this important project” said Snow. “As part of the broader CHGE, I am hopeful our efforts will determine how genetics can influence susceptibility to severe COVID-19, particularly in younger, otherwise healthy people.”

"The critical research being undertaken by Dr. Dalgard, Dr. Snow and the USU team will inform efforts to understand disease severity and susceptibility for pandemic illness. Within the Department of Defense and the Military Health System, the insights gleaned from this work will directly impact Service member health and readiness," said PRIMER director Dr. Clesson Turner.

Dalgard and Snow are also directly involved with the EPICC protocol, being administered through USU’s Infectious Disease Clinical Research Program, which is currently enrolling COVID-19 patients across several military treatment facilities, including Walter Reed National Military Medical Center.

“The American Genome Center at USU is optimally positioned to perform high throughput genomic analyses of COVID-19 patient samples across various studies, and we are particularly enthusiastic to deliver for CHGE and our NIAID colleagues in this highly urgent public health scenario. These genomic data and findings will provide scientific teams new avenues for understanding the genetic and biological basis of this new disease,” said Dalgard.


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