COVID-19: To uncover a signature of patients at risk of developing a severe form of the disease

Which patient is going to develop a severe form of coronavirus? To answer this question, the teams of Frédéric Rieux-Laucat and Mickael Ménager at Imagine have obtained Flash funding from the French National Research Agency (ANR). This signature would make it possible to anticipate the evolution of the disease, along with paving the way to therapeutic avenues.

Published on 17.04.2020

Research Acceleration

Frederic Rieux Leucat & Mick Ménager

While most people with COVID-19 develop only mild disease or a few complications, about 15% require hospitalization and 5% require admission to an intensive care unit. Where does this difference come from? The answer most certainly lies at the heart of our cells, among the immune responses involved in fighting infection by the SARS-CoV2 virus responsible for COVID-19. In the absence of an effective antiviral therapy or vaccine, it is more necessary than ever to understand the pathophysiological mechanisms leading to acute respiratory syndromes (ARDS) in order to:

  • find a signature to identify high-risk patients
  • provide effective therapies to control these serious forms of SARS-CoV2 infections, and reduce the number of patients admitted to intensive care units (ICU).

Where does the cytokine storm come from in patients with severe forms?

Some patients with COVID-19 appear to deteriorate suddenly between days nine and 12 after the onset of the first symptoms, following a runaway immune system response.

"A growing number of indications show that this worsening is caused by a cytokine storm," explained Rieux-Laucat, Director of the Inserm Laboratory of Immunogenetics of Pediatric Autoimmune Diseases.

These small molecules are well known by immunologists since they regulate the activity of the immune system and induce inflammation of tissues.

"Infection with the SARS-CoV-2 virus leads to overproduction of several cytokines such as interleukins 1 and 6 and interferons, mainly type 1,” said Ménager. “This runaway immune system response would lead to hyperinflammation that can cause death. "

Single-cell: Plunging into the heart of genes to better understand the virus

"With single-cell analysis, we are changing scale," said Ménager, who is finalizing the installation at Imagine of a single-cell core facility, equipped with the first device in Europe  — called the Chromium Connect ( — allowing single-cell libraries to be created automatically, produced by 10x Genomics. It's as if until now, researchers have been observing the human body with a microscope that zoomed to 10x, and now they have a 1000x zoom. In one go, they can analyze the expression of thousands of genes on more than 10,000 cells per individual. The idea is to go and look at the expression of immunity genes in about 100 patients with moderate COVID-19, then follow their evolution and do a new analysis in the 5% who will develop ARDS.

American company 10x Genomics is a partner in the COVID-19 project, allowing the installation of a device in a type L3 containment laboratory for the study of blood cells from patients with COVID-19.

By comparing moderate and severe cases of Covid19, the researchers hope to uncover an early warning sign, a molecular signature, to identify those most at risk of developing a severe acute respiratory syndrome (SARS).

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D’où vient la tempête de cytokines chez les patients ayant des formes sévères

L’état des patients atteints de COVID-19 semble se détériorer soudainement, entre le 9e et le 12e jour après l'apparition des premiers symptômes, suite à un emballement du système immunitaire. « Un nombre croissant d’indications montre que cette aggravation est provoquée par une tempête de cytokines », explique Frédéric Rieux-Laucat, directeur du laboratoire Inserm d’immunogénétique des maladies auto-immunes pédiatriques. Or, ces petites molécules sont bien connues des immunologistes puisqu’elles régulent l’activité du système immunitaire et induisent l’inflammation des tissus. « L’infection par le virus SARS-CoV-2 entraîne une surproduction de plusieurs cytokines comme les interleukines 1 et 6 et les interférons de type 1 essentiellement. Cet emballement du système immunitaire entraînerait une hyper-inflammation pouvant causer le décès des patients. » enchaîne Mickael Ménager.


Le single-cell : plongée au cœur des gènes pour mieux comprendre

 « Avec l’analyse par cellule unique, nous changeons d’échelle » décrit Mickael Ménager, qui finalise l’installation à Imagine d’une plateforme single-cell, dotée du 1er appareil – appelée le Connect – en Europe permettant de réaliser des librairies single-cell de façon automatisée, produit par 10X Genomics. C'est comme si jusqu'à présent les chercheurs avaient observé le corps humain avec un microscope qui faisait un zoom X10 et que maintenant ils disposaient d'un zoom x1000. En une seule fois, ils peuvent analyser l'expression de milliers de gènes sur plus de 10 000 cellules par individu. L’idée est donc d’aller regarder l’expression des gènes de l’immunité chez une centaine de patients présentant un COVID-19 modéré, puis de suivre leur évolution et de faire une nouvelle analyse chez les 5% qui vont développer un SDRA. La compagnie américaine 10X Genomics est d’ailleurs partenaire du projet COVID-19, en permettant l’installation d’un appareil dans un laboratoire de confinement de type L3 pour l’étude de cellules du sang de patients atteints de COVID-19.

En comparant avec des personnes non infectées, les chercheurs espèrent ainsi mettre au jour des signes avant-coureurs, une signature moléculaire, pour identifier les personnes les plus à risque de développer un syndrome respiratoire.

This is only the first step in our project. We also plan to decipher the mechanisms leading to this hyperinflammation, as it opens the door to therapeutic avenues.  

Frédéric Rieux-Laucat

How knowledge of rare genetic diseases can shed light on COVID-19

For immune deficiency specialists such as Rieux-Laucat, these observations are reminiscent of monogenic diseases in which abnormal production of inflammatory cytokines and unregulated activation of certain white blood cells, such as monocytes/macrophages, occurs in the context of a storm of inflammatory cytokines, which can lead to fatal multi-organ failure if no treatment is administered in time.

In children with activating mutations affecting genes involved in the detection of intracytoplasmic DNAs, such as the STING gene, abnormal production of inflammatory cytokines such as interferon and IL6 is accompanied by lung damage similar to that of patients infected with SARS-CoV-2, as well as chilblain more recently observed in some Covid-19 patients. In children with genetic defects affecting the ability of T cells to kill an infected cell, macrophage activation and cytokine storm occur following infection with normally non-pathological viruses (in immunocompetent individuals) such as Epstein-Barr virus (EBV). Finally, in adults a macrophage activation syndrome is also observed following viral infections.

While aggressive chemotherapies have long been the standard of care for these macrophage activation syndromes, emerging immunotherapies targeting the cytokine pathway(s) have recently shown their efficacy with limited side effects.

"These new prospects therefore argue in favor of early identification of patients with COVID-19 in whom an overreaction of the immune system may occur and who could benefit from such immunotherapy," said Rieux-Laucat.

Lessons learned from the clinical management of patients with rare genetic diseases could be important today for patients with COVID-19. This is new evidence of the close links between rare genetic diseases and their more common counterparts. Research continues to establish further links with immune deficiency diseases in the event that other therapeutic avenues are discovered that could be useful for patients with COVID-19. A repurposing of treatments already in use and known for other pathologies is indeed a path to be favored in view of the urgency of the situation.