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Common Genetic And Immunological Causes Of Life-Threatening COVID-19 Discovered Through Unprecedented International Collaboration

New York, NY  ·  September 10, 2020

In two new collaborative studies published today in Science, researchers found that nearly 15 percent of young and healthy people who develop severe COVID-19 either have misguided antibodies that attack not the virus, but the immune system itself, or they carry a specific kind of genetic mutation. The patients with severe disease lack type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether the proteins have been neutralized by so called auto-antibodies, or are lacking due to a faulty gene, the findings help explain why some people develop a disease much more severe than others in their age group.

The research is the first to be published out of the COVID Human Genetic Effort, an international project spanning over 50 sequencing hubs, including the New York Genome Center (NYGC), Columbia University’s Zuckerman Institute, and hundreds of hospitals around the world. Led by Jean-Laurent Casanova, MD, PhD, at The Rockefeller University and Helen Su, MD, PhD, at the National Institute of Allergy and Infectious Diseases, the research study recruited patients of many nationalities from Asia, Europe, Latin America, and the Middle East. The results provide a molecular and genetic explanation for nearly 15 percent of critical cases of COVID-19 infections across diverse ancestries. This effort dramatically demonstrated the power of collaboration and data sharing in research directed towards understanding and treating COVID-19-infected patients.

The findings help explain why some people develop a disease much more severe than others in their age group — including, for example, individuals who required admission to the ICU despite being in their 20s and free of underlying conditions. “These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19,” says Dr. Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University and a Howard Hughes Medical Institute investigator. “And at least in theory, such interferon problems could be treated with existing medications and interventions.”

Early in the COVID-19 pandemic the New York Genome Center established the COVID-19 Genomics Research Network with the goal of providing genomic tests and analyses to their New York and New Jersey hospital partners. The objective is to combine the clinical data provided by hospital partners with genomic data generated from patient biospecimens at the NYGC to establish a “data commons” for physicians and scientists to openly access in their efforts to understand the disease and treat virus-infected patients. As a part of that effort, the NYGC joined the international consortium led by Dr. Casanova, which holds weekly meetings in virtually all time zones across the globe.

“The rapid and unprecedented shift of research activities locally and internationally from basic research to COVID-19 related studies has not only united the international scientific community for a common cause, but has led to fundamentally important insights into infectious diseases that have already impacted the current pandemic and will make it possible to be better prepared for the next outbreak,” says Tom Maniatis, PhD, Evnin Family Scientific Director and CEO, NYGC and Isidore S. Edelman Professor of Biochemistry and Biophysics at Columbia University’s Vagelos College of Physicians and Surgeons and Principal Investigator at Columbia’s Zuckerman Institute.

The initial study of the international consortium focused on young and healthy people who develop severe COVID-19 (extreme cases). The new research shows that some of these patients have misguided antibodies that attack the immune system itself, rather than the virus (auto-antibodies), while other patients carry a specific kind of genetic mutation (or inborn genetic error) that diminishes their resistance to infection. In both groups, the end result is basically the same: The severely affected patients have a deficiency in type I interferons, which are produced by human cells in response to virus infection, and triggers viral defenses throughout the body. Interferon production requires a complex cellular signaling pathway consisting of a set of 17 proteins that detect the presence of the virus and prevent it from replicating. Whether these proteins have been neutralized by auto-antibodies, or are less effective because of “in-born” genetic changes in the genes which encode them, “interferon missing-in-action” appears to be a common theme among the subgroup of COVID-19-infected individuals whose abnormally severe disease has thus far been a mystery.

Genetics of COVID-19 outliers
The way SARS-CoV-2 affects people differently has been puzzling. The virus infection can lead to a symptom-free infection, or it can kill in a few days. Dr. Casanova’s research over the past two decades has shown that unusual susceptibility to certain infectious diseases can be traced to single-gene mutations that affect an individual’s immune response.  Since February, the international consortium has been enrolling thousands of COVID-19 patients to determine whether something in their genetic makeup drives the disparate clinical outcomes the disease produces.

In one study, the researchers genetically analyzed blood samples from more than 650 patients who had been hospitalized for life-threatening pneumonia due to SARS-CoV-2, 14 percent of whom had died. They also included samples from another group of over 530 people with asymptomatic or benign infection. The consortium initially searched for differences between the two groups across 13 genes known to be critical for the body’s defense against the influenza virus. These genes are required for cells to produce normal levels of type I interferons. It soon became apparent that a significant number of people with severe disease carried rare DNA sequence variants in these 13 genes, and more than 3 percent of them were actually missing a functioning gene. Further experiments showed that immune cells from these patients did not produce any detectable type I interferons in response to SARS-CoV-2.

Biochemical studies confirmed that the genetic changes detected in individuals with severe outcomes result from defects in the function interferon pathway proteins. For example, Junqiang Ye, PhD, a Research Associate in Dr. Maniatis’ lab at Columbia University’s Zuckerman Institute, carried out biochemical studies on a critical interferon pathway gene called TBK1. He found two cases in which the mutant TBK1 protein was inactive, thus directly demonstrating a functional impact of the COVID-19 disease associated mutation. These findings, along with studies of all of the other interferon pathway genes point to certain medical interventions to consider for further investigation, including treatment with interferon, which is available as a drug approved for use to treat certain conditions such as chronic viral hepatitis.  Both the international consortium and the NYGC New York/New Jersey based COVID-19 Genomics Research Network are continuing to recruit additional patients, and explore new areas of research for additional insights that could be used in the effort to stem the pandemic.

A mysterious auto-immune condition
Careful examination of 987 patients with life-threatening COVID-19 pneumonia, revealed that more than 10 percent produced auto-antibodies against interferons at the onset of their infection, thus disabling the normal anti-virus response. Remarkably, the majority of patients, 95 percent, were men, thus providing an explanation, at least in some cases, for the more severe response to COVID-19 in men compared to women.

Biochemical experiments confirmed that these auto-antibodies can effectively curb the activity of type I interferons. In some cases, the antibodies could be detected in blood samples taken before patients became infected; in others, they were found in the early stages of the infection, before the immune system had time to mount a response.  Fortunately, these auto-antibodies are rare in the general population. Out of 1,227 randomly selected healthy people, only four were found to have the auto-antibodies.

Related Science Publications

Auto-antibodies against type I IFNs in patients with life-threatening COVID-19

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

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