JEAN-LAURENT CASANOVA (NEW YORK)
GENETIC AND IMMUNOLOGICAL CAUSES OF LIFE-THREATENING COVID-19
Jean-Laurent Casanova, MD, PhD
Levy Family Professor, The Rockefeller University
Investigator, Howard Hughes Medical Institute
Head, St. Giles Laboratory of Human Genetics of Infectious Diseases
Senior Attending Physician, The Rockefeller University Hospital
Visiting Professor, Necker Hospital and School of Medicine, University Paris Descartes
Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-
19. We have 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. By testing these and other rare variants at
these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years,
underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts
with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3-
and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia
in patients with no prior severe infection.
Also, interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We
report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had
neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-a (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-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2
infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or
mild SARS- CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients
with auto- Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy
of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at
least 2.6% of women and 12.5% of men.
References:
Zhang Q et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science.
2020 Oct 23;370(6515):eabd4570.
Bastard P et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science.
2020 Oct 23;370(6515):eabd4585.