SARS-CoV-2 Infection Induces Pro-Fibrotic and Pro-Thrombotic Lipid-Laden Foam Cell Formation

SARS-CoV-2 is the causative agent of COVID-19 and long COVID, two illnesses characterized by a dysregulated immune response. Macrophages have long been considered a key component of the dysregulated immune response occurring during severe cases of COVID-19 and long COVID. Using humanized mice implanted with human lung tissue, we demonstrate that macrophage replication is induced by SARS-CoV-2 infection which also promotes macrophage enlargement and the formation of lipid laden cells. Notably, we show that enlarged macrophages display a pro-fibrotic and pro-thrombotic phenotype. Even after immune-mediated clearance of replication competent virus, macrophage numbers remained elevated, and lung fibrosis and thrombi formation were still present. Importantly, we also showed that pre-exposure prophylaxis or early treatment with a SARS-CoV-2 antiviral, EIDD-2801, was able to reduce macrophage expansion and prevent COVID-19 mediated lung pathology such as fibrosis by reducing collagen deposition and decreasing smooth muscle actin, a biomarker of fibrosis. Elevated macrophage numbers were observed in a mouse-adapted SARS-CoV-2 model, and enlarged macrophage were elevated in a non-human primate model of SARS-CoV-2 infection, and in cadaveric human lung samples from SARS-CoV-2 infected individuals. We postulate that SARS-CoV-2 infection induces the production of foam cells which in turn contribute to pathology associated with COVID-19 including thrombi formation. Overall design: Mice with implanted human lung tissue (LOM) were used as an in vivo model to evaluate the infection of lung tissue with the coronaviruses SARS-CoV-2. Viruses were directly injected into the human lung tissue of LOM mice, and lung tissue was collected 2, 6 or 14days after exposure to determine virus titre and/or for analysis by histology, electron microscopy or transcriptome characterization use the GeoMx platform. GeoMX sequencing was completed only on day 0, 2, or 6.