Abstract
In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.
Highlights
1234567890():,; In COVID-19, immune responses are key in determining disease severity
By 14 dpi, cellular influx into alveolar spaces was largely resolved, with fewer neutrophils, macrophages, and lymphocytes observed within the interalveolar septa, while marked hyperplasia of alveolar epithelial cells remained (Supplementary Fig. 2e–n)
Recent patient-centered research on COVID-19 was compromised by three blind spots: (i) biomaterial is usually sampled after hospital admission, the early phase of infection and host response has rarely been investigated. (ii) the bronchoalveolar lavage (BAL) procedure to access the alveolar compartment is too dangerous for non-intubated patients with COVID-19 pneumonia, so that alveolar host responses can hardly be investigated in mild and moderate COVID-19. (iii) Lung tissue can exclusively be harvested after death in COVID-19 patients, precluding from investigations of non-myeloid alveolar or endothelial host responses in early disease, and enabling for analysis of later disease stadium only in case of fatal outcome
Summary
1234567890():,; In COVID-19, immune responses are key in determining disease severity. The enduring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the urgent need for experimental models to rapidly identify pathomechanisms and therapeutic targets of corona virus disease 2019 (COVID-19). While blood of COVID-19 patients is accessible to detailed longitudinal investigation irrespective of disease severity, and bronchoalveolar lavage (BAL) can be safely performed in intubated patients, pulmonary tissue responses remain inaccessible in mild and moderate COVID-19 courses, since lung tissue is only available upon autopsy from patients with fatal disease. Experimental models of COVID-19 are needed, which reflect the complexity of human responses to SARS-CoV-2 infections, including the spatiotemporal dynamics of airway and alveolar infection, local pulmonary immune responses, the activation of systemic inflammatory, complement and coagulation cascades, the impairment of endothelial barrier function, and mechanisms of resilience, resolution, and repair. The disease observed in hamster species primarily affects the lower respiratory tract, which more closely resembles the common courses of human disease as opposed to clinically severely affected transgenic mice, in many of which infection of the central nervous system (CNS) is the predominant manifestation of the disease[15,16]
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