One quarter of severe forms of Covid-19 are explained by a genetic or immunological anomaly

The consequences of Sars-Cov-2 infection are highly variable from one person to another. While most infected individuals are minimally symptomatic or asymptomatic, some develop severe or even critical forms of the disease, with pneumonia requiring a stay in intensive care. How can these disparities be explained? Two new studies published on August 19 in the journal Science Immunology [1] [2] shed major light on this question. They highlight genetic and immunological abnormalities that globally explain nearly 25% of severe forms of Covid-19. This breakthrough is the result of an international collaboration led by Inserm researchers, professors from Université de Paris and physicians from AP-HP at the Human Genetics of Infectious Diseases Laboratory, in its two branches: at Institut Imagine, located at the Necker-Enfants Malades Hospital AP-HP, and at the Rockefeller University in New York. The teams of this laboratory, co-directed by Prof. Jean-Laurent Casanova and Laurent Abel, have shown that all these abnormalities interfere with the immunity controlled by type 1 interferon, the first immunological barrier against viral infections.

Published on 19.08.2021

Research Acceleration

After more than a year of pandemic, the hypothesis of a genetic and immunological predisposition to severe forms of Covid-19 is confirmed. In October 2020, the teams of Prof. Jean-Laurent Casanova and Laurent Abel had already published two studies in the American journal Science [3] [4] explaining 10 to 15% of severe forms of Covid-19. All were due to a deficiency in the type 1 interferon (IFN 1) pathway, a protein usually produced rapidly by the immune system in response to a viral infection and whose main effect is to inhibit the replication of the virus in infected cells. Researchers have shown that at least 3 to 4% of severe forms of the disease have a genetic origin, while 10 to 11% can be explained by the presence of autoantibodies directed against IFN 1 and which block their antiviral action. This discovery was honored by the journal Nature [5] in its top 10 major scientific advances of the year 2020. Two new international studies coordinated by the same laboratory and published on August 19 in the journal Science Immunology provide new scientific data which, added to the previous ones, explain 20 to 25% of severe forms of Covid-19.

TLR7 gene variants involved

In the first publication, the authors identified variants in the TLR7 gene, leading to the development of critical forms, particularly in young patients [1]. The Franco-American team started from the observation that the most severe forms mainly affect men. They therefore focused on what distinguishes the two sexes: the presence of a single X chromosome in men versus two copies in women. In practice, they sequenced the X chromosome of 1202 male patients with a severe form. They then compared all these sequences with each other and with those of a control group who had contracted Covid-19 in asymptomatic or mild forms. Result: in 16 patients (1.1%), the authors identified "loss-of-function" genetic variants of the TLR7 gene. This gene plays a major role in the IFN1 production mechanism. All 16 patients had a deficiency of IFN 1, which prevented their cells from fighting the Sars-Cov-2 infection, thus explaining the severe forms. To avoid ethnic bias and ensure a representative sample, the researchers recruited patients from all over the world, mobilizing 400 research centers in 38 different countries. The results of this cohort are therefore transposable to the general population. The results show that 1.3% of severe forms of Covid-19 in men can be explained by genetic abnormalities of the TLR7 gene. This deficiency is more frequent (1.8%) in patients under 60 years of age.

Deleterious autoantibodies

In the second publication, the authors demonstrated that 15-20% of severe forms are caused by the presence - in the patients' blood - of autoantibodies that specifically target type 1 interferons [2]. In vitro experiments conducted by the team of Charles M. Rice, Nobel Prize winner in 2020, have shown that these antibodies block the protective effect of IFN1 on viral replication. The Sars-Cov-2 virus thus enters cells without resistance and replicates uncontrollably. In 2020, researchers were able to explain 10 to 11% of severe forms of the virus because they focused on patients with a very high level of autoantibodies in the blood. In this new study, they lowered this threshold and included patients with neutralizing levels of interferon up to 100 times lower. The result: autoantibodies that block these low levels of IFN 1 lead to severe lung disease.

Why age is a risk factor 

In order to better understand the distribution of these autoantibodies in the general uninfected population and in particular the influence of age (most cases of severe forms of Covid-19 are found in people over 65 years old), the authors compared more than 34,000 healthy individuals, classified by sex and age group, from the cohorts of Inserm, the Etablissement français du sang, and Cerba Healthcare, a partner of the Human Genetics of Infectious Diseases Laboratory. They made an unexpected discovery: the presence of autoantibodies directed against IFN 1 are very rare before the age of 65 (0.2 to 0.5%) and then increase exponentially with age. They reach 4% between 70 and 79 years of age, and 7% between 80 and 85 years of age. The causes and mechanisms of this increase in the general population remain to be elucidated but it partly explains why age is a major risk factor in the development of severe forms of Covid-19.



[1] X-linked recessive TLR7 deficiency in 1% of men under 60 years with life-threatening COVID-19, T. Asano et al, Science Immunology, 2021.

[2] Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years and account for ~ 20% of COVID-19 deaths, P. Bastard et al., Science Immunology, 2021

[3] Inborn errors of type I IFN immunity in patients with life-threatening COVID-19, Q. Zhang et al., Science, 24 septembre 2020 

[4] Auto-antibodies against type I IFNs in patients with life-threatening COVID-19, P. Bastard et al. Science, 24 septembre 2020