Scientifically Speaking | Knowing how coronavirus hacks cells will help stop it

All vaccines are designed to prompt the immune system to create antibodies that recognise the viral spike protein. But a lesson from India’s second wave is that in addition to vaccines, we need antivirals to help those who have already infected

Many people are now familiar with the spike protein that the Covid-19-causing coronavirus uses to get inside human cells. All vaccines are designed to prompt the immune system to create antibodies that recognise the viral spike protein. But a lesson from India’s second wave is that in addition to vaccines, we need antivirals to help those who have already infected.

A health worker collects a nasal swab sample from a boy for Covid-19 testing at the urban primary health centre, in Bhubaneswar, Odisha. (File photo)

The drugs that are currently available for Covid-19 were created with the purpose of treating other diseases. Consequently, many of these drugs have not lived up to the initial promise. To develop new antiviral drugs, last week, the United States (US) government decided to invest over $3 billion. To thwart the virus, we must find where it is vulnerable to intervention.

Compared to the process of viral entry, there has been less attention paid to what happens once the coronavirus is inside the cell. This phase of the viral life cycle is important because some successful antiviral drugs might prevent intact virus particles from being made and infecting other cells.

Inside the cell, the virus needs to evade the innate immune response and fight for the cell’s resources. But, in many ways, this is where the remarkable capability of the virus to wreak havoc comes into full play. Apart from the spike protein, there are at least two dozen other viral proteins encoded by the SARS-CoV-2 genome.

Proteins are both building blocks and molecular engines that speed up living processes. They are made according to specific instructions in the genetic material. Different proteins do different jobs.

The virus does not possess the ability to make its own proteins and so it must take over the cell’s protein-making machines, known as ribosomes. Ribosome read instructions in RNA to make proteins.

Once viral RNA is inside the cell, it must compete with the cell’s own mRNA. In many ways, viral RNA looks a lot like cellular mRNA, so ribosomes are fooled into making some viral proteins. But the virus needs to ensure that it has preferential access to ribosomes, otherwise it will not be able to increase to massive numbers needed to spread rapidly.

Here’s an analogy for how the coronavirus takes over a cell it has infected. If we think of the cell as hardware and viral RNA as malicious software, gaining entry to the inside of the cell is just the first step. The software must subvert the functioning system so that its instructions are preferentially followed.

We know that the virus prevents ribosomes from making the cell’s own proteins, including tools of the immune system, and, instead, instructs it to make virus parts. How SARS-CoV-2 achieves this has been a mystery until recently.

One of the first viral proteins that is made is called nonstructural protein-1 (NSP1). It is an important weapon in the viral arsenal. Last year, multiple groups showed that NSP1 gums up the channel which is used to read the cell’s own instructions. In addition, immediately after NSP1 is made, it starts to slow down ribosomes, so the cell can’t make proteins needed to minimise viral infection.

But shutting down ribosomes completely would be problematic for the virus since it needs its own RNA to be made into viral proteins. The virus might drain the cell’s resources, but also needs to use what is left of the same resources to make proteins for new viruses.

A paper published in Nature on May 12 by Noam Stern-Ginossar and colleagues shows that the coronavirus destroys the cell’s mRNA and prevents newly created mRNA from getting to parts of the cell where it can be read to make new proteins. By blocking its competition, viral proteins are freeing up ribosomes inside cells for its own proteins to be made.

Last week in research published in Proceedings of the National Academy of Sciences, Peter Cresswell and other researchers showed that another protein NSP14 also helps shut down immune responses inside the cell by interfering with ribosomes.

Using our hacking analogy, the nefarious coronavirus has not one but many kinds of malware that slow down the cellular computer. It shuts down normal programmes, freeing up what’s left of the processor to execute its own instructions to make more viruses.

These new results show why the coronavirus initially gets an upper hand after it infects cells. But this doesn’t mean that it is infallible. The virus also has an Achilles’ heel. While viral proteins are being made, the ribosome slips in reading the viral message by a letter. This slip is known as a frameshift, and it is necessary for the RNA to be “read” properly as coronavirus proteins are made.

A paper published in Science on May 13 by Nenad Ban’s team describes the process of frameshifting with coronavirus RNA in detail. It also shows that antiviral drugs can disrupt this slip. Research is ongoing to exploit this weakness to prevent the coronavirus from hacking the protein-making machinery of cells. Other drugs might target NSP1 and NSP14 and serve as a firewall against these pesky proteins.

Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction

The views expressed are personal