SARS-CoV-2 infection of non-human primates

National Institute Of Allergy And Infectious Diseases

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Abstract

SARS-CoV-2 infection has a spectrum of clinical disease outcomes, ranging from asymptomatic to fatal. The severity of COVID-19 is largely determined by the degree of virus-induced damage and immune-mediated pathology. However, the factors that prevent or promote pulmonary inflammation during SARS-CoV-2 infection are not well understood. Rhesus macaques experimentally infected with SARS-CoV-2 develop mild signs of disease and clear most of the virus within a couple weeks. Accordingly, this species is a useful model for examining the mechanisms of effective viral control and well-controlled inflammatory response that occurs in most individuals with SARS-CoV-2 infection. Immunosuppression with glucocorticoids (GC) has been widely used to treat the most severe cases of COVID-19. GC treatment reduces mortality in COVID-19 patients requiring mechanical ventilation. However, GCs can also prolong viral shedding and increases the risk of death for those not requiring respiratory support. Thus, GC therapy is beneficial in severe COVID-19 but may impair resolution of SARS-CoV-2 infection due to suppression of anti-viral immune responses. Synthetic GCs (e.g. dexamethasone and prednisolone) are broadly immunosuppresive, but the cellular mechanisms responsible for impaired SARS-CoV-2 clearance with GC therapy are unknown. In this project we use rhesus macaques to test the hypothesis that GC impair control of SARS-CoV-2 infection in an otherwise resistant host and to investigate the immunological effects of GC treatment during acute SARS-CoV-2 Delta infection. In the study, the animals were pre-treated with GC prior to infection and then maintained in GC throughout the study. Day 14 post infection was chosen as the pre-determined endpoint for necropsy. We measured lung inflammation with 18FDG PET/CT imaging and performed single cell RNA sequencing and spectral flow cytometry analysis on samples collected from the blood and airways of rhesus macaques receiving GC treatment before and after SARS-CoV-2 infection. We find that GC treatment reduced PET/CT imaging based indicators of lung inflammation. Immunologically, GC treatemnt profoundly impaired the early accumulation of plasmacytoid dendritic cells, eosinophils and gamma delta T cells in the airways. This was associated with ~135 fold higer peak viral titers in the airways and higher viral loads in lung draining lymphm nodes at necropsy. These results show that in GC treatment can exacerbate mild SARS-CoV-2 infection in resistant hosts and provide potential immunologic mechanisms of impaired viral control.