points in common with a rare genetic disease open a new avenue

A large majority of people infected with the new coronavirus develops a light form of Covid-19. However, among the patients so far screened, 15% require hospitalization and 5% will have to be admitted to intensive care for a severe form. To improve the prognosis of these patients, it is essential to understand if they have specificities.

Except for any pathologies associates who complicate their clinical situation (excluding the causes of comorbidities and advanced age), the defense system of their organism also seems to be involved. In fact, about a week after the start of the symptoms, the worsening of the respiratory condition observed in some is not solely related to virus : it is also associated with a immune response exaggerated.

Dysregulated immune response to inflammation

We talk about " cytokine storm ", A phenomenon linked to the excess production of certain mediators ofinflammation (the cytokines), including interleukin-6 (IL-6). Other markers of response to infections, such as interfering (IFN), on the other hand, seem to be greatly reduced in severe forms. In addition, the virus can be detected in the cells of the blood, whereas this is not the case in patients who suffer from mild forms, suggesting poor control of the infection.

This answer immune particular has a certain resemblance to that which is observed in the childhood vasculopathy associated with Sting (or Savi, acronym for Sting Associated Vasculopathy with Onset in Infancy), a rare genetic disease, in particular responsible for lung damage.

This observation led the team to Frédéric Rieux-Laucat (Institut Imagine, Paris) to collaborate with the hospital services of Cochin hospital in Paris (in particular with Benjamin Terrier in internal medicine and Solen Kernéis in infectiology) taking care of patients with Covid-19. Their objective: to use existing knowledge on Savi to help better fight against severe forms of the new viral disease.

Similarities between Covid-19 and Savi

Frédéric Rieux-Laucat explains that "Savi patients have an activating mutation in the uncomfortable Sting (Stimulator of Interferon Genes or Interferon Gene Stimulator) which leads to the excess production of IFN and inflammatory cytokines like IL-6. It also leads to the infiltration of immune cells, including lymphocytes B, within lungs, in a way mimicking a constant respiratory viral infection. Clinically, this disease is characterized by pulmonary or skin damage, such as frostbite or, in extreme forms, a gangrene extremities. "

However, it is now established that some Covid-19 patients may have frostbite. " It therefore seems that the antiviral responses of patients with a severe form of Covid-19 have common features with those of Savi patients. "

To verify this hypothesis, the researcher's laboratory is now carrying out work using blood samples, taken from samples taken as part of care in the Covid-19 wing of the internal medicine department of Cochin hospital. They will allow a very fine characterization of the cells immune involved in the response that takes place in patients, as well as the level of cytokines that their body produces.

By comparing the rates measured in hospitalized patients with severe or critical pulmonary disease to those associated with mild or moderate forms, they wish to identify specific mechanisms with prognostic value.

The trail of genetic vulnerability explored

"In a few weeks, we may be able to establish a signature of the deregulated pathways in the various immune cells, which would constitute a risk of complication. It could also lead to personalized therapeutic perspectives. " Indeed, there are already many drugs available to modulate the molecular pathways mediated by cytokines, such as those of IFN or IL-6.

Furthermore, the hypothesis of a predisposition genetics of patients with severe forms is evaluated by the laboratories of Jean-Laurent Casanova and of Laurent Abel, also at the Imagine Institute in Paris. Their core business is precisely to characterize genetic alterations involved in severe forms of viral infections.

In the past, they have already identified a hundred mutations, the result of which is a modification of the immune response to a viral infection (loss or enhancement of certain response pathways), such as tuberculosis, herpes where the influenza.

By sequencing of genome of patients with Covid-19, they are now seeking to identify genetic features which accentuate the severity of the infection by SARS-CoV-2 or, conversely, which limit the appearance of symptoms, sometimes to their complete absence (case of asymptomatic people despite certain exposure to infection).