Many viruses adapt to new hosts by changing their genes. This rapid adaptation is the result of (1) quick replication cycles (sometimes as short as 30 minutes!), (2) viral genome-copying enzymes that make frequent errors, some of which confer helpful new properties, and (3) genetic exchange between different virus strains. Influenza A viruses (IAV) are famous for these quick changes that yield subtly different virus strains that cause seasonal influenza outbreaks, or more drastically altered pandemic strains that can have devastating impacts on human health worldwide, like the 2009 swine flu outbreak.
Virus genomes encode proteins required for taking over cells, hiding out from immune systems, and building new viruses. Viruses don’t produce these proteins on their own; instead, they plug into pre-existing host cell machinery to get the job done. Proteins are produced from a chemical code stored in our cells called ribonucleic acid (or RNA for short). This code, when read in groups of three (triplets), produces the building blocks of proteins, commonly called amino acids. The host cell protein-making machinery knows how to read the code by searching for the “start” triplet. When the cell machinery sees the start triplet, it begins reading the code until it hits the “end” triplet, releasing the completed protein.
The host cell is not defenceless against viral takeover of its protein-making machinery. Indeed, one of the first things that the cell tries to do upon infection is shut off the protein-making machinery to prevent viral takeover. It’s a race for control. In turn, sneaky viruses have evolved their own ways to undermine the host. IAV, for instance, can produce additional proteins by using a different start triplet. How is this possible if our cell machinery only recognizes the original start triplet? In this case, the virus takes advantage of an obscure ‘backup’ system that the cell has for making proteins using different start triplets, which expands the protein-coding capacity of the genome. Like the famous Jeff Goldblum line from Jurassic Park, “Life finds a way”.
In a study conducted by Machkovech and co-authors, the team infected cells with IAV to evaluate how the virus uses different triplets to make proteins. Using a method that essentially takes a snapshot of the protein-making process, they found that IAV evolved to reduce the number of triplets that can be used as possible start sites. While this may seem counter-intuitive, proteins produced from these different start triplets may be easily recognized by the immune system, which would be bad for the virus. The authors reasoned that the virus reduces the number of different start sites as it adapts to mammalian cells to evade the immune system. Interestingly, in the course of this study the authors accidentally discovered a new viral protein that had not been recognized before (this is one of the best aspects of fundamental research….serendipity!)
Overall, these results demonstrate that alternate translation initiation plays a significant role in shaping the protein-coding capacity of both virus and host during influenza infection. Machkovech and co-authors showed that alternative protein production increased cell immune response efficiency and directed influenza virus evolution to escape the immune system.
Summary written by: Alina Butova
To read the full article, please click the following link:
Comprehensive profiling of translation initiation in influenza virus infected cells
Heather M. Machkovech, Jesse D. Bloom, Arvind R. Subramaniam