Why a SARS-CoV-2 infection is asymptomatic in some people and deadly in others is a mystery that has been at the forefront of researchers’ minds for the last six months. The Casanova lab at the Rockefeller University has been studying this same question, with other pathogens, for years.
In January, the lab turned their attention to COVID-19. And now, in collaboration with colleagues, they have published two papers that shed significant insight into why there is such immense clinical variability between individuals. The findings also may provide the first molecular explanation for why more men than women die from COVID-19.
The work is published in back-to-back Science papers. The first paper is titled, “Inborn errors of type I IFN immunity in patients with life-threatening COVID-19,” and the second, “Auto-antibodies against type I IFNs in patients with life-threatening COVID-19.”
Since February 2020, Helen Su, MD, PhD, a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH; and Jean-Laurent Casanova, MD, PhD, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University, and their collaborators, have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.
The researchers, led by Qian Zhang, MD, a research associate in the Casanova lab, discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the body’s defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2.
Specifically, they found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection.
The authors showed that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2.
Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. The 101 patients had “neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs.” The auto-antibodies neutralize the ability of type I IFNs to block SARS-CoV-2 infection in vitro. In addition, the authors noted that these auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only four of 1,227 healthy individuals.
Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies or for a genetic reason were produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.
These findings are the first published results from the COVID Human Genetic Effort, an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals.
