A detailed study of a SARS-Cov-2 protein, Nsp1, with a central role in weakening the host anti-viral immune response shows that it effectively shuts down production of proteins in the host. Although SARS-Cov-2 features additional inhibitors of host innate immune defenses, targeting the interaction of this protein, Nsp1, with the host may be an important therapeutic strategy, the authors say. A major virulence factor of SARS-CoVs, including the SARS-CoV-2 virus causing the current COVID-19 pandemic, is the protein Nsp1.
Upon infection, it suppresses protein production in the host ,including production of proteins active in cellular anti-viral defense mechanisms, by binding to the cell's protein production machinery, the ribosome. Targeting the pocket on the ribosome that Nsp1 binds to could be an important potential therapeutic strategy. Here, Matthias Thoms and colleagues set out to structurally characterize the Nsp1 of SARS-CoV-2 bound to the ribosome. As part of their approach, they tested the ability of a mutant form of Nsp1, known as mt-Nsp1, to affect protein production related to host immune response, in both in vitro and in vivo experiments. The mutant version did not bind in the same way, the authors showed, and did not shut down host translation (or protein production). Through further experiments, the authors' results demonstrate that SARS-CoV-2 Nsp1 almost completely prevents production of various immune molecules that fight viral infection, including interferons.
"Our data establish that one of the major immune evasion factors of SARS-CoV-2, Nsp1, efficiently interferes with the cellular translation machinery resulting in a shut-down of host protein production," the authors write.
Even while noting that important questions remain to be addressed in this space, they say their data may provide a starting point for rational structure-based drug design targeting the interaction between Nsp1 and the ribosome.
Thoms, M., et al. (2020) Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. doi.org/10.1126/science.abc8665.