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

Chronic COVID-19 is characterized by persistent viral RNA and sustained interferon (IFN) response which is recapitulated and required for pathology in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice. As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology. Here, we describe SARS-CoV-2 uptake in tissue resident human macrophages that is enhanced by virus specific antibodies. SARS-CoV-2 replicates in these human macrophages as evidenced by detection of double-stranded RNA, subgenomic viral RNA and expression of a virally encoded fluorescent reporter gene; and it is inhibited by Remdesivir, an inhibitor of viral replication. Although early IFN deficiency leads to enhanced disease, blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade by injecting anti-IFNAR2 in vivo in the chronic stages of disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the chronic disease itself. ### Competing Interest Statement RAF is an advisor to Glaxo Smith Kline and Zai labs.