SARS-CoV-2 nsp1 puts translation on mute across mammalian species

In late 2019, an unknown coronavirus made the leap from animals to humans. That incident might have gone unnoticed—except that the virus was able to infect human cells, replicate, and spread rapidly from person to person. In fact, most so-called spillover events—when pathogens move from one species to another—do not lead to pandemics like COVID-19, because several conditions must align for a virus to successfully establish itself in the new host.

For a successful spillover event to occur, the virus’s original host (also known as the reservoir host) must come into close contact with another species while shedding large amounts of virus. Second, the virus must be able to enter the new host’s cells having never met the recipient previously. This requires the host cells to have a compatible receptor that allows the virus to bind and slip inside. Finally, the host cells must support viral replication and subsequent transmission. For example, SARS-CoV-2 evolved to bind with high affinity to the human ACE2 receptor, enabling it to enter human cells and hijack their machinery to reproduce.

Horseshoe bats are the widely accepted reservoir hosts of SARS-CoV-2. Viruses like SARS-CoV-2 don’t harm these bats but are thought to have made the leap to humans through spillover events like the ones described above. Once inside a cell, viruses need to take control of host machinery to replicate. They do this by encoding viral proteins that disable key parts of the host immune response. One such protein is non-structural protein 1 (nsp1), an early viral protein that blocks protein synthesis in human cells, preventing the translation of critical innate immune proteins. 

Given that bats are the natural reservoir of SARS-CoV-2 and do not get sick from it, members of the Campbell and Lapointe labs in the Fred Hutch Basic Sciences Division, along with the Veesler lab at the University of Washington, set out to investigate the role of nsp1 in bat cells. Nsp1 is known to be a major SARS-CoV-2 virulence factor that suppresses the innate immune response by blocking protein synthesis in human cells. “Recent studies have suggested that unique characteristics of the bat innate immune system allow them to tolerate viruses that are highly pathogenic to humans and other animals, such as coronaviruses (CoVs),” the researchers explained. The team found that nsp1 broadly inhibits protein synthesis across several mammalian species, including both bat and human cells. These findings were recently published in Cell Reports.

Nsp1 works by binding directly to the ribosome—the cell’s protein-making machine—and blocking translation. This prevents infected cells from producing immune proteins like interferons, which are key to mounting a defense against viruses. Although nsp1’s ability to block translation in human cells is well established, the team wanted to know if it functions the same way in bats. They used Rhileki cells, a kidney cell line derived from Blyth’s horseshoe bat (Rhinolophus lepidus), as well as cells from Tadarida brasiliensis—a species from the same bat suborder that diverged from R. lepidus about 63 million years ago.

The results were striking: nsp1 inhibited translation in all tested cell types, including human, R. lepidus, and T. brasiliensis cells. To understand how it does this, the team used cryo-electron microscopy (cryo-EM) to study the structure of the R. lepidus ribosome. 

They found that both the bat and human ribosomes were highly similar, and that nsp1 bound to the bat ribosome in the same way it binds to human ribosomes, effectively shutting down protein synthesis.

To further test the breadth of nsp1’s activity, the researchers examined its ability to block translation in cells from other mammals, including dogs, cats, minks, deer, and pigs. Nsp1 successfully blocked protein synthesis in all tested cell lines except pig cells. Pigs were used as a control, as previous studies have shown that although SARS-CoV-2 can enter pig cells, it cannot replicate within them.

This study revealed that nsp1 works just as effectively in bat cells as in human cells, pointing to a shared viral strategy for suppressing the immune system across species. More importantly, its broad inhibitory function makes nsp1 a promising candidate for future antiviral therapies.

The spotlighted work was funded by the National Institutes of Health, a Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund, a Shurl and Kay Curci Foundation Graduate Scholarship award and a Pew Biomedical Scholars award. 

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs Melody Campbell and Christopher P. Lapointe contributed to this research. 

Gen R, Addetia A, Asarnow D, Park YJ, Quispe J, Chan MC, Brown JT, Lee J, Campbell MG, Lapointe CP, Veesler D. (2025). SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals. Cell Rep.