Published on 19.03.2020
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.
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.