RA-COVID-19 V3 - Recherche - Action Coronavirus disease 2019 - Vague 3

Lung cell senescence as a target to combat COVID-19 – SENOCOVID

Submission summary

The new coronavirus disease 2019 (COVID-19) due to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a major socio-economic and health burden. Understanding the biological mechanisms underlying the greater susceptibility of the elderly and of those with comorbidities to severe forms of COVID-19 is essential for developing preventive and therapeutic strategies. Cell senescence is a basic aging process that strongly contributes to health deterioration and disease. Based on our recent demonstration that influenza A virus (IAV) infection induces lung-cell senescence, worsening the virus-induced lung pathology, we hypothesize that SARS-CoV-2 infection is also associated with lung-cell senescence. If so, this might be important for the treatment of COVID-19, particularly in individuals exhibiting numerous senescent lung cells at baseline. We have defined two objectives.

First, we intend to (i) monitor the accumulation of senescent cells in the lungs during SARS-CoV-2 infection, (ii) determine the nature and molecular (transcriptomic) signature of the senescent cells, and (iii) assess the impact of baseline senescence on viral replication and pathogenesis. Two complementary animal models will be used: mice expressing human angiotensin-converting enzyme 2 (hACE2), the cell entry receptor for SARS-CoV-2; and hamsters, a natural host for SARS-CoV-2. Two conditions mimicking physiological situations and known to induce the expansion of senescent cells will be studied. Young adult hACE2-expressing mice will be treated (or not) with bleomycin, to induce senescence and lung fibrosis. In the hamster model, we will compare young with elderly animals. In both conditions, we will assess senescent-cell accumulation, viral replication, lung alterations, inflammation, and health outcomes.

Second, we shall evaluate the effects of senescent cell depletion during SARS-CoV-2 infection on disease outcomes. Pre-existing cell senescence conditions (bleomycin-treated hACE2 mice or aged hamsters) will be prioritized. Two senolytic drugs will be administered: navitoclax and the FOXO4-DR1 peptide, which selectively induce apoptosis of senescent cells with different modes of action. The consequences of senescent cell depletion on viral replication, lung damage, systemic inflammation, and death will be assessed. We expect that pharmacological elimination of senescent cells by senolytic drugs will inhibit senescence-associated inflammation and significantly reduce disease severity.

The major strengths of this proposal include strong preliminary data (from the influenza model), feasible objectives (models and tools are available), and the complementary expertise provided by the consortium’s three members. The project has the potential to generate important scientific knowledge (on infection, senescence, and pathogenesis) and a rationale for finding new ways to treat COVID-19.

Project coordination

François TROTTEIN (INSTITUT PASTEUR DE LILLE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IMRB Institut Mondor de Recherche Biomedicale - équipe 10 - Biologie du système neuromusculaire
IPL INSTITUT PASTEUR DE LILLE
CRCL Centre de Recherche en Cancérologie de Lyon

Help of the ANR 149,580 euros
Beginning and duration of the scientific project: June 2020 - 12 Months

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