Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice.

In the MISTRG6 model of COVID-19, SARS-CoV-2 virus peaks at four days post infection (dpi) and then subsides to levels 1000-fold lower which persist for weeks. Similar to infected humans, viral RNA persists at high levels for several weeks. Chronic interferon has previously been associated with disease severity and impaired recovery in influenza infection. To test whether a viral RNA-dependent type I IFN response was a driver of chronic disease, we treated SARS-CoV-2 infected MISTRG6-hACE2 mice with Remdesivir, anti-IFNAR2 antibody or a combination of the two starting 7dpi, by which time viral titers are already significantly reduced. As Remdesivir inhibits viral RNA dependent RNA polymerase (RdRp) while anti-IFNAR2 targets the IFN-dependent cascade downstream of infection, we hypothesized that targeting these two elements which act sequentially would attenuate the hyperactive immune/inflammatory response and resolve immunopathology. As a control, we also treated mice with dexamethasone, one of the few treatments that significantly reduced hospitalization and mortality in the clinic. We previously showed dexamethasone in our model reversed many aspects of immunopathology in infected MISTRG6-hACE2 mice. Remdesivir and anti-IFNAR2 alone were partially therapeutic and reversed chronic weight loss and many aspects of immune activation. Combined therapy of Remdesivir and anti-IFNAR2 however achieved rapid weight recovery and profound suppression of the immune inflammatory response as effectively as dexamethasone suggesting a synergistic or additive effect of Remdesivir and anti-IFNAR2 in the chronic phase of infection.