X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Abstract

Interindividual clinical variability in the course of severe acute re-spiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast, ranging from silent infection to lethal disease (1). The greatest risk factor for life-threatening coronavirus disease 2019 (COVID-19) pneumonia is age, with a doubling in risk every 5 years from the age of 5 years onward and a sharp rise after the age of 65 years (2, 3). Other epidemiological risk factors, including common genetic vari-ants, have only modest effects, with odds ratios of <2 and typically <1.5 (2). One intriguing observation is the about 1.5 times higher risk in men, which seems to be age independent (2–4). The COVID Human Genetic Effort consortium (www.covidhge.com) has enrolled an international cohort of patients, with the aim of investigating genetic and immunological causes of life-threatening COVID-19 pneumonia. We previously tested the hypothesis that critical influ-enza and critical COVID-19 can be allelic (5–7) and showed that life-threatening COVID-19 pneumonia can be caused by rare in-born errors of autosomal genes controlling Toll-like receptor 3 (TLR3)– and interferon (IFN) regulatory factor 7 (IRF7)–dependent type I IFN immunity (8). These disorders were found in 23 men and women aged 17 to 77 years (mean, 48 years). Four unrelated patients aged 25 to 50 years had autosomal recessive IFNAR1 (n = 2) or IRF7 (n = 2) deficiency. These patients had no previous history of severe viral illness, including influenza pneumonia, implying trance for critical influenza. These findings revealed that TLR3- and IRF7-dependent type I IFN immunity is essential for host defense against SARS-CoV-2 infection in the respiratory tract.We also found preexisting neutralizing auto-antibodies (auto-Abs) against type I IFN in at least 10% of the patients from this cohort (9). These auto-Abs were found in 101 patients, mostly men (95%), and older members of the cohort, which included patients with in-born errors, as they were aged 25 to 87 years (mean, 65 years). These findings have been replicated in five other cohorts (10–15). These auto-Abs predated SARS-CoV-2 infection and were highly likely to be causal for critical COVID-19 pneumonia, because (i) they were ound in samples drawn before infection in some patients (9), (ii) they were found in about 0.3% of the general population before the age of 65 years (9), (iii) they were absent from patients with asymp-tomatic or paucisymptomatic (mild) SARS-CoV-2 infection (9), (iv) they were of childhood onset in patients with various disorders—including autoimmune polyendocrinopathy type I—known to be at very high risk of life-threatening COVID-19 (16), and (v) they have been shown to underlie a third of adverse reactions to the live atten-uated viral vaccine for yellow fever (17). Collectively, these studies showed that type I IFNs are essential for protective immunity to SARS-CoV-2 in the respiratory tract but are otherwise unexpected-ly redundant. Auto-Abs against type I IFNs also provide a first ex-planation for both the biased sex ratio and the higher risk of critical COVID-19 in patients over the age of 65 years. Here, we tested the hypothesis that critical and unexplained COVID-19 pneumonia in men may be due to rare variants on the X chromosome.