In some hospitalized patients, Covid-19 is characterized by a severe form due to an inflammatory state. This has been widely studied to the detriment of other biomarkers such as the decrease in the number of lymphocytes which nevertheless play a key role in the immune system. The process which is at the origin of this lymphopenia has just been highlighted and the researchers also demonstrate that it is reversible.
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Nearly 60% of patients hospitalized for Covid-19 have lymphopenia, i.e. a decrease in the number of lymphocytes circulating in the blood compared to normal values. The mechanisms explaining this condition have long remained poorly understood. In a new study, researchers from Inserm and the University of Paris in collaboration with teams from Nîmes (CHU de Nîmes), Canada (Laval University) and Portugal (University of Minho and Hospital of Braga) revealed a phenomenon of programmed cell death referred to as ” apoptosis which would explain the loss of lymphocytes in these patients.
They also showed in vitro that this process is reversible through the use of caspase inhibitors, molecules which block the action of enzymes responsible for apoptosis. These results, published on January 22, 2022 in the journal Cell Death & Differentiationmake it possible to consider new therapeutic avenues for patients with severe forms of Covid-19.
Covid-19 is a disease characterized by great clinical heterogeneity. While most infected people are asymptomatic or show mild symptoms, others develop severe forms of the disease. Research on hospitalized patients has so far focused on the inflammatory state that characterizes severe forms, but less on other biomarkers. However, among these patients, 60% of them have lymphopenia, that is to say that the number of T cells CD4 in their blood is below normal values.
The team of Inserm researcher Jérôme Estaquier, within research unit 1124 (Inserm/University of Paris) and Laval University in Quebec, looked into this phenomenon. Scientists have long worked on AIDS, a pathology for which a low number of CD4 lymphocytes in the blood is precisely a marker of poor prognosis. So here they were able to put in application their knowledge of these processes in the field of Covid-19.
In their work, the researchers studied blood samples from patients hospitalized from April to June 2020 with Covid-19 (some of them in intensive care) and compared them to healthy donors. They thus demonstrated that having lymphopenia was correlated with the presence of several biomarkers of severity.
Reversibility of the programmed cell death process
They also showed that a process of programmed cell death, apoptosis, is at the origin of the disappearance of T lymphocytes in hospitalized patients with Covid-19.
With these molecules, the process of T cell apoptosis is also reversible in the case of Covid-19
In an attempt to block this process, the researchers then relied on previous work carried out in the field of HIV on animal models, in which they had shown that the administration of these molecules, called caspase inhibitors, succeeds in stopping apoptosis, restoring CD4 lymphocytesand to prevent the appearance of AIDS.
They show here that with these molecules, the process of apoptosis of T cells is also reversible in the case of Covid-19.
The results of this study funded by the Fondation Recherche Médicale et AbbVie France and Canada open up new therapeutic avenues for the early treatment of hospitalized patients with lymphopenia. “The idea now is to put in place clinical tests phase 1 to test the safety of caspase inhibitors in humans. T cells are the backbone of immune system. Thus, these molecules could have a long-term usefulness for patients presenting with lymphopenia when entering the hospital. “, emphasizes Jérôme Estaquier.
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