The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.

S evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic human coronavirus to cross the species barrier into the human population during the past 20 years (1-3). SARS-CoV-2 infection is associated with coronavirus disease (COVID-19), which is characterized by severe respiratory distress, fever, and cough and high rates of mortality, especially in older persons and those with underlying health conditions (3). The World Health Organization (WHO) declared SARS-CoV-2 a pandemic on March 11, 2020 (4), and by April 8, a total of 1,447,466 confirmed cases and 83,471 deaths from SARS-CoV-2 had been reported worldwide (5). Human-to-human transmission of SARS-CoV-2 is efficient, and infected persons can transmit the virus even when they have no, or only mild, symptoms (3). Because no antiviral drugs or vaccines are available, virus containment and prevention of infection are the current highest priorities. To limit virus spread, effective hand hygiene is crucial. Therefore, easily available but efficient disinfectants are needed. WHO's guidelines for hand hygiene in healthcare suggest 2 alcohol-based formulations for hand sanitization to reduce the infectivity and spread of pathogens (6). WHO's recommendations are based on fastacting, broad-spectrum microbicidal activity, along with accessibility and safety. The original WHO formulations failed to meet the efficacy requirements of European Norm 1500 in previous tests (7). However, Suchomel et al. (8) suggested modified versions with increased concentrations of ethanol: 80% (wt/ wt) (85.5% [vol/vol]; formulation I), or isopropanol, 75% (wt/wt) (81.3% [vol/vol]; formulations II). Later, they complemented these by reducing the glycerol concentrations (9). We previously showed that these modified WHO formulations were able to inactivate severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV; 10), which are related to SARS-CoV-2. Current recommendations to inactivate SARS-CoV-2 were translated from findings of other coronaviruses (11). To evaluate whether these alcohol-based disinfectants also effectively inactivate SARS-CoV-2, we tested different concentrations of the original and modified WHO formulations I and II (6,9), ethanol, and 2-propanol for virucidal activity.

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Programmed ribosomal frameshifting is a key event during translation of the SARS-CoV-2 RNA genome allowing synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal mRNA channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.

Zoonotic coronaviruses (CoVs) are substantial threats to global health, as exemplified by the emergence of two severe acute respiratory syndrome CoVs (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome CoV (MERS-CoV) within two decades 1-3. Host immune responses to CoVs are complex and regulated in part through antiviral interferons. However, interferon-stimulated gene products that inhibit CoVs are not well characterized 4. Here, we show that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in immune cells were highly susceptible to a murine CoV-mouse hepatitis virus. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic immune cells, higher splenic viral burden and reduction in global antiviral gene pathways. Accordingly, we found that constitutive Ly6e directly protects primary B cells from murine CoV infection. Our results show that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo-knowledge that could help inform strategies to combat infection by emerging CoVs. Coronaviruses (CoVs) are enveloped RNA viruses with broad host tropism and documented capability to cross the species barrier to infect humans 5. The mammalian innate immune response controls CoV infection partly through the action of interferons (IFNs) 4,6,7. IFNs inhibit viral infection by inducing hundreds of genes, many of which encode antiviral effectors 8. The IFN-stimulated genes (ISGs) that inhibit CoV infection are not well