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How Covid-19 evades the immune system

After more than three years since its beginning, the Covid-19 pandemic still wreaks havoc around the world, with increasingly more immune-evasive variants emerging in various countries. An aspect of SARS-CoV-2 that makes it so infectious and challenging to control is its ability to outwit the body’s innate, as well as acquired (through prior infection or vaccination) immune defenses. 

Now, by using a groundbreaking technique known as serial femtosecond X-ray crystallography, a team of researchers led by the Arizona State University (ASU) has examined a viral protein called NendoU that appears to be responsible for the virus’s tactics of immune evasion.

“Our study focuses on how Covid-19 hides from the immune system using the NendoU protein,” said study lead author Rebecca Jernigan, a postdoctoral researcher in Biodesign at ASU. “As we better understand the structure and mechanics of NendoU, we have a better idea of how we can design antiviral drugs against it.”

Viruses have evolved a variety of complex strategies to evade the body’s defense mechanisms. In the case of SARS-CoV-2, the protein NendoU helps the virus hide from the immune system, in plain sight. Once a viral particle binds to a receptor on a cell’s surface, it inserts its genetic material into the cell, causing it to manufacture multiple copies of the viral genome that consists of RNA. When the viruses replicate within cells, their growing RNA structure produces a tail at the end, known as a poly-U tail.

Although human cells are equipped with fine-tuned sensors for detecting invading RNA viruses – because the poly-U tail gives away their identity as foreign invaders, allowing the immune system to attack them – SARS-CoV-2 is highly adept at using its NendoU protein to bind with, then cut-off the poly-U tail, and thus causing the virus to be less visible to the immune system.

The scientists discovered that the NendoU protein acts through a two-step process. First, its more rigid half binds to the active site of the substrate – in this case, a citrate molecule – while the flexible half also binds citrate (or the RNA), but less tightly. However, once the rigid half cleaves the RNA strand, it releases the strand, and becomes flexible. At the same time, the flexible half switches to a rigid state and the cycle is repeated. This scissor-like movement of NendoU’s two main components helps to erase the telltale signal of the virus’s presence within the cell, disabling an appropriate immune response. 

“This work is so exciting as it shows for the first time that the differences in flexibility of the protein play an important role in the functional mechanism,” said senior author Petra Fromme, the director of the Biodesign Center for Applied Structural Discovery at ASU. “This will be critical for development of drugs against NendoU, with potential to reveal the presence of the virus to the immune system, which can then react and hinder serious infections.”

The study is published in the journal Structure.

By Andrei Ionescu, Staff Writer

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