Tricky ways viruses become more dangerous
By: Haley Harrington, Indiana University
Alphaviruses are a family of viruses that cause fever, arthralgia, and rashes worldwide. I primarily study an alphavirus called Sindbis Virus, which is spread by mosquitos typically in tropical areas around the globe. Alphaviruses, and viruses in general, have very small genomes (alphaviruses-8 genes) compared to humans (20,000-25,000 genes) and bacteria (~4,000 genes). These genes encode for proteins that are used to make the structure of the virus, as well as promote viral infection within the host organism.
My research focuses on ways that the alphavirus can expand its otherwise small genome and ways that the virus controls which proteins are being made at a specific time during infection. This is achieved through Programmed Ribosomal Frameshifting (PRF), which is a mechanism that many viruses use to produce two different proteins from the same gene. PRF occurs in a process called translation where a gene within the genome is converted into a protein product which performs a specific function. The players involved in this include: the mRNA gene transcript, the growing protein product, an mRNA secondary structure, a slippery sequence the ribosome, and a pulling force on the protein chain.
Think of this process as a factory production line with a machine that is programmed to repeatedly stamp a word onto wooden blocks that are lined up on a conveyor belt. Here, the programming is the viral gene which tells the machine, the ribosome, one specific word to stamp on the blocks, which represent the protein product (1 gene = 1 protein). Once one block has been stamped, the conveyor belt moves forward with just enough room to stamp the next block, and so on.
Now imagine this production line is programmed to stamp “DAN” onto thirty blocks that are all lined up on the conveyer belt. The assembly is moving along fine and stamping “DAN” onto the blocks when suddenly, the PRF event occurs. You can image this as a ceiling tile falling onto the line to pause production (mRNA secondary structure), while the conveyor belt is encountering an excess of slippery oil (slippery sequence) and a worker bumping into the lever that controls the conveyor belt speed and slowing it down (pulling force). These three events result in a shifting of where the machine is stamping the line of blocks, such that it begins stamping “D-AND-AND” onto the product instead of making the programmed “DAN-DAN”.
In this example, a -1PRF has occurred, where the machine (ribosome) has slipped backwards by 1 letter and is now producing blocks stamped with “AND”, representing a distinct protein product. Within the factory we have many different assembly lines that are programmed to produce “DAN” blocks, but some of these assembly lines encounter a PRF event to produce “AND” blocks. In this way, two protein products are made from the same mRNA gene transcript, expanding the number of protein products produced from one gene.
While this analogy isn’t perfect, I hope it represents that viruses can make two proteins from the same gene. Previously this mechanism was thought to only include the slippery sequence (oil) and the mRNA secondary structure (ceiling tile), however, we’ve identified the first example of a pulling force (the worker bumping into the lever) contributing to -1PRF.
Why do we care about this phenomenon? PRF is utilized in many viruses and is important for viral infection. There has recently been a surge in different players in this process as scientists continue to find new ways that viruses use PRF to expand their genome and enhance their infectivity. This process is an excellent target for drug development, and the better we understand this process, the more likely it is that developed antivirals will be effective. This is especially important for the Sindbis alphavirus that I study, as there are currently no antivirals or vaccines in use.