The hidden war between viruses and host cells has influenced the evolution of all life on earth. For millions of years, viruses have acquired and refined weapons to undermine cell defenses and redirect cellular processes to the task of viral replication. Surviving cells created defenses to stave off initial attacks and “remember” attacks, so more vigorous and specific defenses could be engaged if the same virus was faced again. This arms race between viruses and host cells is at the heart of this story.
Viruses are parasites that need to access cell machinery to replicate. The process of making proteins, known as “translation”, is exceedingly complex and energy-intensive. This is why viruses are entirely dependent on cell translation machinery. Thus, protein synthesis represents a major focus of the arms race between viruses and cells. Cells that “sense” that they are infected shut off the synthesis of proteins and increase production of antiviral proteins that can stop viral replication and activate antiviral defenses in nearby cells.
One of the most important parts of the antiviral response in humans is interferon-dependent immunity. Interferons are proteins that trigger antiviral defenses in adjacent cells. Upon encountering interferons, these cells prepare for potential infection by shutting off protein synthesis and activating an enzyme called RNAse L that degrades viral messenger RNA (mRNA) before it can be decoded into proteins by ribosomes. These coordinated defenses restrict the ability of viruses to make proteins. Moreover, interferons can strike a decisive blow against viruses by activating a cellular suicide mechanism known as apoptosis, which sacrifices the infected cell to prevent the spread of infection. Finally, interferons play an important role in attracting immune cells to the site of infection to activate global antiviral immune responses and establish “memory” that is critical to prepare for future infections.
The COVID-19 pandemic has focused attention on the mechanisms how SARS-CoV-2, undermines host defenses and successfully replicates and spreads. One of the proteins that plays a big role in this process is called nsp1; this protein prevents infected cells from sending message to the immune system by blocking the production of interferon. The process of viral proteins blocking the production of host cell antiviral proteins is commonly known as “host shutoff”. The mechanisms of host shutoff usually include degrading cell’s mRNAs that encode antiviral proteins and disabling key components of the host protein synthesis. New research indicates that nsp1 uses both strategies to shut off the production of host antiviral proteins.
Ribosomes are cellular components that read the instructions in mRNA and build proteins. To begin ribosome must assemble on an mRNA template. Once mRNA is in the ribosome, it can efficiently ‘slide’ along an mRNA and build a protein. However, the SARS-CoV-2 nsp1 protein binds to the ribosome and blocks it, stopping the ribosome from reading the instructions from the mRNA. In this way, nsp1 prevents the host from creating antiviral proteins and initiating an immune response.
In addition to preventing ribosomes from reading mRNAs, nsp1 can also destroy mRNAs to prevent them from being read in the future. All cellular mRNAs have a feature, called a ‘CAP’ that protects them from degradation. When nsp1 binds to ribosomes it also causes the CAP to be removed from mRNAs. Previous work suggests that viral mRNAs are not targeted by nsp1, allowing them to accumulate and be translated by a small pool of active ribosomes. Ongoing studies of SARS-CoV-2 host shutoff mechanisms will help us identify important aspects of the virus-host interface that can be exploited by future vaccines and antiviral drugs. Akin to the game hide-and-seek: when you finally understand your opponent’s mindset, you will always know where to find them.
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