期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2117198119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The COVID-19 pandemic and the ever-evolving variants of SARS-CoV-2 are taking a toll on human health. Despite the successful rollout of vaccines, effective therapies are still urgently needed. Our studies here showing that Nsp1 selectively blocks translation of host but not viral proteins by proper coordination of its N- and C-terminal domains to advance our understanding on SARS-CoV-2 pathogenesis. Our finding that stem-loop 1, a highly conserved sequence in the SARS-CoV-2 5′ UTR, is necessary and sufficient for bypassing Nsp1-mediated shutdown led to the design of antisense oligonucleotides targeting this sequence that make viral translation susceptible to Nsp1 shutdown, interfere with viral replication, and protect SARS-CoV-2–infected mice. This strategy of turning SARS-CoV-2’s own virulence against itself could be harnessed therapeutically.
SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.
