Genetics, a compass to explain severe forms of viral infections

Exposure to a virus provokes very different responses from one individual to another. In a review of the literature published in Science on 26 November, Laurent Abel and Jean-Laurent Casanova, co-directors of the Human Genetics of Infectious Diseases Laboratory at the Imagine Institute, look back at more than twenty years of research into the genetic origin of this inter-individual variability

Published on 26.11.2021

Research Acceleration

The history of medicine is full of clinical cases that have led to spectacular advances in the understanding of human biology. The study of a small number of patients, or even a single patient, can shed light on the function of a biological entity, lead to the identification of the cellular and molecular pathways involved in the disease and clarify the physiopathological mechanism. These are all essential steps in the discovery of new therapeutic targets and the implementation of targeted treatments. This approach is at the heart of the experimental approach of the Human Genetics of Infectious Diseases Laboratory, co-directed by Jean-Laurent Casanova and Laurent Abel, at the Institut Imagine (Inserm, AP-HP, Université de Paris). Since the creation of their laboratory in 2000, their teams have been able to identify and describe numerous circuits essential to the immune system's response to various infectious agents (viruses, bacteria, fungi) based on the study and description of patients suffering from single-gene mutations.

A pioneering hypothesis

In a review published on 26 November in the American journal Science, the research duo take stock of more than two decades of discoveries on genetic predisposition to viral infections [1]. "We know that exposure to a virus is a necessary but not sufficient condition for becoming ill," says Laurent Abel. This variability between individuals is an enigma for scientists. But several barriers are about to be removed. As early as the 1990s, the two scientists put forward the hypothesis that certain severe forms of viral infections can be explained by an alteration in immunity caused by single-gene defects. This pioneering idea was viewed with some scepticism by the scientific community at the time, but has now become a new paradigm.

It must be said that the scientific evidence has been accumulating in recent years, as shown by the 68 studies cited in the Science review . The researchers list about fifty mutations that explain the occurrence of severe forms following various viral infections. "The organs most affected are the brain, the lungs and the skin," explains Laurent Abel. "Most of the time the consequences of such viral infection are benign, but they can be disastrous in patients with these mutations."

Emblematic examples include paediatric encephalitis due to herpes virus infection (present in the majority of the population) [2], severe pneumonia after infection with respiratory viruses such as Influenza (flu) or more recently SARS-CoV-2 (COVID-19), or even the tree-man syndrome after papillomavirus infection.

Towards a new biology 

"Our approach consists of starting with genetics: we identify the monogenic mutations that cause these severe forms. From this, we characterise the entire circuit of the immune response and the inflammation that may result, which then enables us to understand which stage has been damaged by the mutation," explains Laurent Abel. In 2015, the researchers identified a mutation in the IRF7 gene [3] in a patient suffering from a severe form of influenza. This mutation caused a defect in the production of type 1 interferons (IFN), the first immunological barrier against viral infections. Thanks to this discovery, the teams of Jean-Laurent Casanova and Laurent Abel were able to make a comparison with the severe pneumonia observed during the COVID-19 pandemic: some patients suffering from these severe form of the disease had this same mutation in the IRF7 gene.

Genetics is like a compass that indicates which biological pathway to look at and which cog in the mechanism might be altered  

Laure Abel , co-director of "Human genetics of infectious diseases" laboratory

But the story does not end there. The study of these genetic abnormalities led the researchers to identify other functional defects that also affect the type 1 IFN pathway in severe patients without a mutation. These patients had an abnormal amount of autoantibodies that neutralised the action of type 1 IFNs. "By characterising the molecular pathway of type 1 IFNs, we were able to identify other types of defects and elucidate about 20% of the severe forms of COVID-19 [4]," explains Laurent Abel. "Genetics is like a compass that indicates which biological pathway to look at and which cog in the mechanism might be altered in severe forms". Understanding rare genetic abnormalities can therefore be extended to more frequent cases and thus benefit a larger number of patients. The researchers are convinced that other viral infections could benefit from similar genetic approaches. " [This approach] is giving rise to a new biology and medicine', they write in Science.

[1] J-L. Casanova & L. Abel, Science, 374, 1080, 2021.

[2] 10.1126/science.112834610.1126/science.1139522

[3] M.J. Ciancanelli et al., Science, 348, 448-453, 2015.

[4] 10.1126/science.abd457010.1126/science.abd4585