“‘Tis the season to be jolly… Fa la la-la-la, la-la la la.”
Jolly – really?!
I dread the holiday season. I don’t dread it because of the snow, or because of the forced family interactions, not even because of the Christmas songs on loop on the radio stations – but because it is the common cold and the flu season.
How can I be jolly when I am sneezing, coughing, congested, tired, feverish, and aching all over my body? How can I get into the holiday spirit when I can’t enjoy the smell or taste of my Thanksgiving or Christmas dinner? It is almost 2020 and we still don’t have a cure for the common cold. This leads me to wonder:
Will there ever be a cure for the common cold?
I first want to make sure that you know that there is a difference between the common cold and the flu. Although they have eerily similar symptoms, though subjectively milder for the cold, both infectious diseases are caused by different viruses. The common cold is caused by any of a multitude of viral strains, with rhinoviruses being the most common culprit, whereas the flu is caused by the influenzavirus A-C. Determining whether you have the cold or the flu is currently difficult, even if you go to see a medical professional. This is due to the fact that the laboratory tests that doctors use to identify the virus are somewhat accurate only at the early stages of infection and can give many false positive or negative results. These laboratory tests have poor detection accuracy because viruses have the ability to rapidly mutate and change their molecular structure, which is part of the answer to “will there ever be a cure for the common cold?”
Human rhinoviruses (HRV) were first discovered in the 1950s when scientists were trying to determine the cause of the common cold. HRVs are one of the smallest viruses in nature, about 30 nanometers in diameter, yet they are able to make a person who is millions of times larger feel sick. They can do so because once a single virus particle enters one of our cells, the virus can then make millions more virus particles so that it can spread and infect other cells. You can think of a viral infection like a snowstorm. At first you see a single snowflake falling, which hits the ground and rapidly melts. But as time passes, the frequency of snowflakes falling increases, leading to snow accumulation on the ground. Ultimately, the snow covers all exposed surfaces and creates chaos, even shutting down roads and entire cities, which is analogous to what the cold does to our bodies.
Furthermore, as the virus is making more copies of itself, the virus also introduces mutations at random, which can alter the structure of the virus particle. This creates a diverse population of HRVs; analogous to “no two snowflakes are alike.” As I mentioned, this variability in structure can make it difficult to detect the virus accurately and it is also a reason why it is difficult to make a vaccine or develop other therapeutics to treat the common cold. To add to the complexity, HRVs are made up of more than 100 viral serotypes. You can think of viral serotypes as different types of snow, the powdery kind when the snow is falling, the slush type as it is melting, or the icy type when it gets frozen. Each type of snow is different in composition but still snow; all 100 plus HRV serotypes differ in structure but are all HRV capable of causing the common cold. Even though we don’t have a cure for the common cold, we are not defenseless; our bodies are able to fight the virus and clear us of infection after a couple of days.
How does the body fight the cold virus?
The innate and adaptive immune response are our main tools of defense against the common cold. Our immune system makes antibodies that target HRV particles to combat infection by focusing on epitopes on the proteins located on the surface of the virus.1Jacobs, S.E., D.M. Lamson, K. St. George, and T.J. Walsh. (2013). Human rhinoviruses. Clin Microbiol Reviews. 26:135-162. https://www.ncbi.nlm.nih.gov/pubmed/23297263 Epitopes are the areas of the virus particles that the immune system recognizes as a toxin. This initiates the production of antibodies that are specific to these areas to fight the virus and clear us from infection. Our adaptive immune system is also able to remember these epitopes and produce these antibodies faster for future infections with the same virus.
Then why do we keep catching the cold almost every year?
First, there is a delay from the moment the virus first enters our body until the immune response is activated to re-make these antibodies. This gives HRV the opportunity to enter a cell to make more copies of itself and change its structure to hide, or change the epitopes that were previously recognized, which would prevent detection of the virus and allow it to escape our immune system to carry on with infection.
When our immune system produces antibodies targeting the surface proteins of HRV, it does so for that specific HRV serotype, but as I mentioned before, there are more than 100 HRV serotypes. Therefore, if your body is infected with a different HRV serotype, then the previously made antibodies cannot recognize the surface proteins of the new HRV serotype, leading to the development of another common cold episode. Unfortunately, this is where the snowstorm analogy is no longer applicable; the antibodies our bodies make are not like the salt mixture that is used to melt and get rid of all types of snow.
So, is that it? Are we doomed to not be jolly due to the common cold for the rest of time?
Latest efforts in developing a cure for the common cold have shifted to targeting HRV when it’s inside the cell. Although viruses outnumber living organisms by 1031 – and that is a low estimate – viruses are not alive and heavily depend on their host to propagate.2Microbiology by numbers. (2011). Nat Rev Microbiol. 9:628. https://www.nature.com/articles/nrmicro2644 And although viruses, including HRV, have the ability to rapidly mutate between each replication round, their dependency on host cell proteins limits where the variations can occur. Therefore, some scientists are investigating how viruses interact with our cells’ proteins in hopes that disrupting those interactions will be a promising way of treating infectious diseases. Recently, a group of researchers found a cellular protein called SETD3 that is required for infection by Enteroviruses, which are a broad group of viruses that include HRVs. They determined that SETD3 specifically interacts with a viral protein of several enteroviral species to promote viral replication. When the interaction was disturbed, the number of viral particles being produced was dramatically reduced.3Diep, J., Y.S. Ooi, A.W. Wilkinson, et al. (2019). Enterovirus pathogenesis requires the host methyltransferase SETD3. Nat microbiol. 4:2523-2537. https://www.ncbi.nlm.nih.gov/pubmed/31527793 This suggests that SETD3 can be a novel target to potentially decrease viral infections from Enteroviruses, including HRVs, to cure the common cold!
But what if we could have a cure for the common cold like the salt mixture used during snowstorms? Scientists are also working on developing “broadly neutralizing antibodies” and “multi-specific antibodies” to target viruses. Broadly neutralizing antibodies work by binding epitopes that are conserved in viral surface proteins of many viral strains.4Caskey, M., F. Klein, and M.C. Nussenzweig. (2019). Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nat Med. 25:547-553. https://www.ncbi.nlm.nih.gov/pubmed/30936546 Multi-specific antibodies reduce the chance of viral escape by making antibodies that can bind to more than one epitope at a time.5Labrijn, A.F., M.L. Janmaat, J.M. Reichert, and P.W.H.I. Parren. (2019). Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 18:585-608. https://www.ncbi.nlm.nih.gov/pubmed/31175342 That way, if a virus mutates one epitope, the antibodies can still bind to another epitope and stop the virus. These “next generation” antibodies are another promising avenue to target HRV infections.
So, my long-winded answer to “will there ever be a cure for the common cold?” is a hopeful YES! Through new discoveries made by scientists researching the mechanisms of viral pathogenesis, our knowledge will expand and uncover new targets to treat the common cold so that we are only infected by the “holiday spirits” during this time of year.
