SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801

All coronaviruses known to have recently emerged as human pathogens probably originatedin bats(1). Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.

Automated summary

The study suggests that bats may be the source of coronaviruses that can be directly transmitted to humans. Using the LoM model, efficient replication of SARS-CoV, MERS-CoV, SARS-CoV-2, and two SARS-like bat coronaviruses in human lung tissue was demonstrated. Infection with SARS-CoV-2 predominantly targets human lung epithelial cells and induces a sustained inflammatory response. The broad-spectrum antiviral agent EIDD-2801 significantly inhibits SARS-CoV-2 replication in vivo, showing potential for prevention and treatment of COVID-19.