COVID-19: several Imagine teams mobilize

Research is at the heart of the war against the coronavirus epidemic. Several Imagine teams are working to fight COVID-19.

Published on 19.03.2020

Research Acceleration

In the face of COVID-19, medium and long-term responses will come from research. In that respect several teams are using their knowledge of genetic diseases to better understand COVID-19 and how patients respond differently to the infection.

Why do some people develop more severe forms of the disease?

Jean-Laurent Casanova* and Laurent Abel** labs are exploring our genome to try to understand these differences. “The variability observed during exposure and infection with SARS-CoV-2 makes it very likely that there are human genetic factors influencing the response to this virus," explains Laurent Abel. Very few studies have been conducted to date on the coronavirus family infection host genetics, most of them using mouse models infected with the SARS-CoV, which was responsible for the 2003 epidemic. In this regard, mice whose Ticam2 TLR adaptor protein involved in the immune response was inactivated were found to be highly susceptible to SARS-CoV infection".

Together, these two teams have already identified some 100 genetic alterations that may explain susceptibility to serious infections including herpes, tuberculosis and influenza. “It is by studying the genome of a young girl, who at the age of two and a half had contracted a very severe form of influenza requiring hospitalization in pediatric intensive care unit, that we found the origin of this vulnerability," recalls Jean-Laurent Casanova. She had inherited a mutated allele of the gene coding for the regulatory factor IRF7 from each of her two parents. This resulted in a loss of interferon production, leading to a cascade of disruptions in her defence system against infection by the influenza virus.”

Today, thanks to the French cohort of patients with COVID-19, and thanks to an international recruitment, they want to uncover the genetic variants - those small differences in the sequence of our genome that make us unique - involved in the development of the disease.

Thanks to their expertise in whole exome sequencing (WES), they will initially focus on identifying the variants that have a strong impact on the development of particularly severe clinical forms in individuals, sometimes young, infected with SARS-CoV-2.

They will then study the genetic basis for resistance to the SARS-CoV-2 infection in individuals who have been unquestionably exposed to the virus and yet are neither ill nor even infected with the virus.

As with many other viral infections, their hypothesis is that genetic variants play an important role in the different stages of the SARS-CoV-2 infection, particularly in the development of infection following exposure and in the occurrence of severe clinical disease in infected individuals. Another objective will be to look for variants associated with nasopharyngeal secretion of the virus in asymptomatic infected persons, i.e. to identify persons who show no signs of infection but may transmit the virus. This is an essential step in restricting spread.

What if the severe forms of COVID-19 are akin to interferonopathies?

This is the hypothesis that Solen Kernéis, Physician at Hôpital Cochin (AP-HP) and Lecturer at Université de Paris, and Benjamin Terrier, Professor of Internal Medicine at Hôpital Cochin (AP-HP), wish to test.

Interferonopathies are a group of diseases characterized by hyperactivation of interferons (IFN), proteins produced following a viral infection. Frédéric Rieux Laucat***'s team at Imagine is a specialist in this field. It was therefore quite natural that he was approached by the two carriers of this project because patients suffering from severe forms of COVID-19 could present an overexpression of genes dependent on type 1 interferon (IFN1). "In these patients, clinicians are observing lung lesions that suggest an excess antiviral response to type 1 interferon. This mechanism may be responsible for the worsening of the condition of patients requiring intensive care hospitalization," said the Researcher.

Reception 1er chantillons COVID

On Thursday, March 19, 2020, Frédéric Rieux-Laucat's lab received the first sample from a patient with COVID-19 in order to evaluate the antiviral response to type 1 interferon. The objective is to determine within one month whether differences really exist between patients with COVID-19 hospitalized in the conventional sector and patients with COVID-19 hospitalized in intensive care for acute respiratory distress syndrome and uninjured subjects. “Beyond information on the fate of the disease, the idea would be to be able to provide targeted treatment to the patients most at risk, explains Frédéric Rieux-Laucat. Interferon 1 activates the Janus kinase signaling pathway (JAK-STAT), a pathway for which there are inhibitors already available in clinical therapy.”


"The specific treatments for COVID-19 will come from research that will intimately decipher the disease, its mechanisms and identify the flaws that will allow us to defeat it. To fight the spread of COVID-19 and save lives, Imagine has at the same time decided to close down operationally most of its research laboratories, while leaving open, of course, those who are mobilized in COVID-19 research in the face of the urgency of the epidemic," says Professor Stanislas Lyonnet, Director of the Imagine Institute.

In the same state of mind that animates the laboratories and the Imagine platform, which have mobilized for research directly related to the epidemic, some doctor-researchers, interns in research training, have come forward as volunteers to support the healthcare teams.


*Jean-Laurent Casanova is Professor at Université de Paris/Hôpital Necker-Enfants malades AP-HP and Rockefeller University in New York and also Director of an Inserm research lab at the Imagine Institute and the Howard Hughes Medical Institute in New York.

**Laurent Abel is co-founder of the Laboratory of Human Genetics of Infectious Diseases, an Inserm international lab organized in two branches, one at Rockefeller in New York and the other at the Imagine Institute.

*** Frédéric Rieux-Laucat is Director of Research at Inserm and heads the Lab of Immunogenetics of Pediatric Autoimmune Diseases at the Imagine Institute.

 Ils étudieront ensuite les bases génétiques de la résistance à l'infection par le SRAS-CoV-2, chez les individus exposés au virus de façon indiscutable, et qui pourtant ne sont ni malades ni même infectés par le virus.

Car comme pour nombre d’autres infections virales, leur hypothèse est que les variants génétiques joueraient un rôle important dans les différentes étapes de l'infection par le SRAS-CoV-2, en particulier dans le développement de l'infection suite à l'exposition et dans la survenue d'une maladie clinique grave chez les personnes infectées. Un autre objectif consistera à rechercher les variants associés à une sécrétion nasopharyngée du virus chez les personnes infectées asymptomatiques, soit à identifier les personnes ne présentant aucun signe d’infection, mais pouvant transmettre le virus. Une étape essentielle pour restreindre la propagation.


Et si les formes sévères de COVID-19 s’apparentaient aux interféronopathies ?

C’est l’hypothèse que souhaitent tester Solen Kernéis médecin à l’hôpital Cochin (AP-HP) et Maître de conférence à l’université de Paris et Benjamin Terrier, professeur de médecine Interne à l’hôpital Cochin (AP-HP).

Les interféronopathies sont un ensemble de maladies caractérisées par une hyperactivation des interférons (IFN), des protéines produites à la suite d’une infection virale dont l’équipe de Frédéric Rieux Laucat** à Imagine est spécialiste. C’est donc tout naturellement qu’il a été sollicité par les deux porteurs de ce projet car les patients atteints de formes graves de COVID-19 pourraient présenter une surexpression des gènes dépendants de l’interféron de type 1 (IFN1). « Chez ces patients, les cliniciens observent des lésions pulmonaires qui suggèrent un excès de réponse antivirale à l’interféron de type 1. Ce mécanisme pourrait être responsable de l’aggravation de l’état des patients qui nécessitent une hospitalisation en réanimation » explique le chercheur.

Reception 1er chantillons COVID

Le jeudi 19 mars 2020, le laboratoire de Frédéric Rieux-Laucat a reçu le 1er échantillon d’un patient atteint de COVID-19 afin d’évaluer la réponse antivirale à l’interféron de type 1. L’objectif est d’ici un mois de déterminer si des différences existent réellement entre les patients atteints de COVID-19 hospitalisés en secteur conventionnel et les patients atteints de COVID-19 hospitalisés en réanimation pour un syndrome de détresse respiratoire aiguë et des sujets indemnes. « Au-delà des informations sur le devenir de la maladie, l’idée serait de pouvoir faire bénéficier d’un traitement ciblé les patients les plus à risque, explique Frédéric Rieux-Laucat. Car l’interféron 1 active la voie de signalisation des Janus kinases (JAK-STAT), une voie pour laquelle il existe des inhibiteurs déjà disponibles en thérapeutique clinique. »

« Les traitements spécifiques contre le COVID-19 viendront de la recherche qui, seule, permettra de décrypter intimement la maladie, ses mécanismes et d’identifier les failles permettant de la vaincre. Pour lutter contre la propagation du COVID-19 et sauver des vies, Imagine a en même temps décidé de fermer opérationnellement la plupart de ses laboratoires de recherche, tout en laissant ouverts, bien sûr, ceux qui sont mobilisés dans les recherches sur COVID-19 face à l’urgence de l’épidémie », déclare le Pr Stanislas Lyonnet, directeur de l’Institut Imagine.

Dans ce même état d’esprit qui anime les laboratoires et la plateforme d’Imagine qui se sont mobilisés pour des recherches directement liées à l’épidémie, Certains médecins-chercheurs, internes en formation de recherche, se sont manifestés comme bénévoles pour venir en renfort des équipes soignantes.

*Jean-Laurent Casanova est professeur à l’Université de Paris/Hôpital Necker-Enfants malades AP-HP et à l’Université Rockefeller à New York et aussi directeur d’un laboratoire de recherche Inserm à l’Institut Imagine et au Howard Hughes Medical Institute à New-York.

*Laurent Abel est co-fondateur du Laboratoire de génétique humaine des maladies infectieuses, laboratoire international de l’Inserm organisé en deux branches, l’une au Rockefeller à New York et l’autre à l’Institut Imagine.

** Frédéric Rieux-Laucat est directeur de recherche à l’INSERM et dirige le laboratoire d’immunogénétique des maladies auto-immunes pédiatriques à l’institut Imagine.