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    Oral Communication

    Immunothrombosis

    Host-Defense

    OC 66.2 - Neutrophil extracellular trap induced thrombosis contribute to tissue damage but not to virus resolution during a respiratory infection

    Tuesday, June 27, 2023
    15:00 – 15:15 ET
    Room: 524
    Session Available As: On-Demand
    Background: Thrombosis and activation of neutrophils are bystanders of pulmonary virus infections. Elevated markers for neutrophil activation, especially neutrophil extracellular trap (NET) formation, are a risk factor for poor outcome in patients with SARS-CoV-2 infection. However, it is unclear whether NET themselves are beneficial and required to counteract virus propagation or a tissue-damaging consequence of inflammation. To answer the role of NETs during a respiratory virus infection, we used a murine betacoronavirus model.

    Aims: Characterization of thrombus formation and determination of the role of NETs during a betacoronavirus infection

    Methods: C57Bl/6 mice were infected with the murine mCoV-A59. Lungs were collected 2, 4 and 10 days after infection, and thrombus formation and virus burden were analysed. Animals were treated with GSK484 to prevent NET formation, DNase to remove formed NETs and OM-85 to preactivate the innate immune system.

    Results: Thrombus formation occurred rapidly and stayed stable until day 10. Day 2 thrombi were platelet-rich and thrombi at day 10 were positive for NETs. We found persistent inflammation and profound tissue damage at day 10, even though we observed virus resolution in the lung at this time point. Prevention of NET formation using GSK484 lead to reduced tissue apoptosis at day 10 with no negative effect on virus clearance. In contrast, using DNAse to remove NETs did not show amelioration of tissue damage. OM-85 treatment prevented NET formation and tissue damage and reduced viral burden.

    Conclusion(s): We describe a biphasic process of lung thrombosis development during a coronavirus infection. Whereas early phase thrombi are platelet rich, late phase thrombi are NET derived. Prevention of NETs with GSK484 improved tissue protection without preventing virus clearance. Our data indicate that NETs are involved in long term organ damage and development of long COVID symptoms with no significant role during initial virus clearance.

    Learning Objectives:

    • describe direct and indirect long term lung tissue damage upon a respiratory virus infection.
    • understand that NETs do not contribute to virus resolution but damage surrounding tissue.
    • delineate that increased numbers of neutrophils do not correlate with tissue damage, if they are not activated.