When the flu hits, it typically hits hard and fast. At first, you might only notice a slight cough and some sniffles and then, before you know it, you’re unable to get out of bed. The fever, sore throat, chills, muscle aches, and overall exhaustion take over your body and you’re done for — at least for a few days, if you’re lucky.
Influenza (aka “the flu”) is a dreadful virus that’s seriously contagious and seemingly unavoidable for some. In fact, several types of flu virus strains exist in any given year and their effects on the body can range from mild to severe, in some cases resulting in hospitalization, even death. And, despite our efforts to keep up with this menacing little bug, it outsmarts us every year by mutating into a new form. How it does this and how our bodies react to it, however, are not entirely understood. To better understand the interplay this virus and others have on our cells, researchers are turning to the study of epigenetics.
Epigenetics is the study of changes in gene expression – heritable during cell division – that do not involve changes to the underlying DNA sequence. These changes are also influenced by age, the environment, lifestyle, and health. Understandably, viruses that infect cells also impact the epigenetic control of their host cells. Some viruses may even alter the epigenome. We know that DNA viruses use their host’s transcription factors, along with epigenetic regulators, to affect their own epigenetic control of gene expression which then extends to host gene expression. At the same time, our cells try eliminating the viral infection by using similar mechanisms, transcription factors, and epigenetic modifications.  Yet, even with what we do know about this virus, as well as many others, there is still much that we don’t know, especially regarding the epigenetic mechanisms involved in viral evasion. However, what scientists are currently finding is leading the way to the improvement of our understanding of epigenetics’ role in most viral-cell interactions.
The ever-changing flu virus
Most of the influenza viruses we hear about today are actually just different versions of the same virus. For example, the bird flu, swine flu, and human seasonal flu are all essentially strains of the H1N1 virus.  This virus, in particular, gets plenty of media attention and has also been linked to the deadly Spanish Flu outbreak of 1918, as well as other major influenza epidemics of recent times. By constantly evolving new traits, this seemingly simple organism, made up only of a nucleic acid and a protein coat, manages to evade our immune system’s defenses and can even jump between species — but, oddly enough, not without the help of its host. And to survive and propagate (its only purpose), it must adapt and change for each species or individual it encounters. With virus adaptations constantly occurring, eventually new strains evolve. This can happen in two ways. People get infected with the virus and develop antibodies against it. Then, the virus responds by making small genetic changes and, over time, the accumulated changes make the virus unrecognizable to known antibodies. This is called an antigenic drift. A more dramatic change that can occur is called an antigenic shift. This is when the virus changes genetically in such a way that it is able to jump from one species to the next. The avian flu (aka “bird flu”) is an example of this. Unfortunately, when this happens, as it does abruptly, we are unprepared for it, and therefore unprotected from the virus. While antigenic drifts are common, a shift happens only occasionally. 
Flu makes use of epigenetics
In a healthy person, the immune system is equipped to handle millions of bacteria, microbes, viruses, toxins, and parasites that invade the body — and it does this daily. But, the flu virus is craftier. Rather than overpowering the immune system, it succeeds by “tricking it”. An epigenetic way it can do this is by producing a protein that mimics the tail of a histone. Researchers at The Rockefeller University found that the immunosuppressive NS1 protein of the influenza A virus (H3N2) contained the same sequence of amino acids as the tail domain of a DNA packaging protein in humans called histone H3. Histones play an important role in gene activation and the tails provide a scaffold for the assembly of protein complexes that control gene activity. NS1’s ability to copy the histone H3 tail allows it to access the core of the gene regulatory machinery, target the PAF1 transcription elongation complex (hPAF1C), and block the antiviral gene function.  The NS1 protein is found in a majority of influenza A viruses (those generally responsible for the large flu epidemics), but their main sequence varies from strain to strain. Some flu strains such as the H1N1 virus do not appear to have an NS1 tail. It may be the diversity of the NS1 tail that explains how viruses can go undetected for some time within the human body. While more research is needed, the findings from this study could be applied to the development of new epigenetic drugs specific to influenza anti-inflammatory responses.
The influenza virus’ main mission is to get inside a cell where it can release its own genetic material. Normally, the outer membrane of the cell keeps intruders out. But the flu virus is covered with special proteins called hemagglutinin that can bind with the sialic acid on the host cell’s membranes, allowing it entry inside a cell where it can easily wreak havoc. However, before it can get to this point, it must have already beaten most of the host’s standard defenses. An essential component of immunity is a host’s ability to produce type I interferons (IFNs). These proteins help regulate the activity of the immune system. To produce IFN responses, hosts use pattern recognition receptors (PRRs). PRRs include Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) that can sense the presence of viral nucleic acids and other invading microbes. The flu virus, however, has developed a way to suppress this response. Researchers have learned that an influenza A virus uses its NS1 protein to bind directly to the E3 ubiquitin ligase TRIM25, inhibiting expression and thereby suppressing RIG-I signal transduction — a modification that is necessary for IFN production in response to viral infections.  Although the precise mechanism of how this is done remains unclear, research demonstrates that this viral protein can directly interfere with IFN response and emphasizes the vital role of TRIM25 in modifying antiviral defenses. 
Host epigenetic response
The flu is something we are all familiar with during certain times of the year. It is one of the most common viral infections that affect humans. Every year, anywhere from 5 to 20 percent of the US population will get the flu and more than 200,000 will be hospitalized with flu-related complications.  These complications are usually due to the immune system inflammatory response. While necessary to eradicate invading pathogens, a severe immune response can sometimes do more bad than good. Epigenetic research on how our bodies react to this virus on a cellular level may help uncover what makes influenza so detrimental.
When the influenza virus enters the body, it makes its way toward the respiratory tract. As it breaches the surface of a cell and releases its own RNA into the nucleus, it sets off the body’s alarm system (See PRRs above). This signaling then results in the production of interferons (IFNs), cytokines, and chemokines to counteract the invasion and induce an antiviral state. However, they also serve to amplify proinflammatory responses. Inflammation must then be controlled carefully by the host in order to prevent any detrimental effects.  In a study investigating epigenetic modifications implicated in host antiviral defense after influenza A virus infection, researchers found that changes in DNA methylation levels were involved in elevating certain proinflammatory genes. They discovered that cyclooxygenase-2 (COX2), a modulator of inflammation, and lambda 1-interferon (IFN-λ1), a proinflammatory cytokine, were both overly expressed in subjects infected by the virus. Specifically, they found that COX2, as well as PGE2 (COX2-derived prostaglandin E2), were activated by the downregulation of enzymes DNMT3a and DNMT3b mediated by microRNA, miR29. The resulting COX2 activation consequently increased the potent antiviral activity of IFN-λ1 in an effort to protect host cells from the infection. Interestingly, this activity occurred right after viral infection and then miR29 expression promptly diminished once the signaling network had been activated. Further investigation is needed to fully understand the delicate process of maintaining DNA balance during proinflammatory responses. However, the relationship between COX2 and IFN-λ1, previously not known, suggests that IFN family members and the inflammation network may not act independently and that epigenetic modifications play a role in the signaling pathway during viral infections. 
In a similar study, researchers replicated four different types of the influenza A virus in human lung epithelial cells and compared changes in promoter DNA methylation levels. What they found was that increased production of cytokines (hypercytokinemia) was linked to changes in promoter DNA methylation of certain inflammatory genes during viral infection. These genes included CXCL14, CCL25, CXCL6, and interleukines IL13, IL17C, IL4R. While the changes in DNA methylation varied across different strains of the virus, researchers noted that the decrease in DNA methylation correlated with increased expression in the genes studied. They also noted that cells infected with the highly pathogenic H5N1 influenza virus (Asian Avian Flu) exhibited the most dramatic decrease in promoter DNA methylation levels. Although more research is needed in determining exactly how these mechanisms regulate host inflammatory gene expression, the findings from both studies highlight the significance of epigenetics in understanding the interactions involved in viral-host immune response. 
More research to fight flu
Over the years, scientists from various fields have made significant contributions to influenza research: from studies investigating the make-up of the virus itself, to how it causes disease, new diagnostics, vaccines, and approaches to mitigate a potential pandemic. Still, this virus, like many others, continues to be a challenge. The influenza virus is notorious because it is highly contagious, causing recurring epidemics and global pandemics, and because of its potential to be fatal. Yet, it is also unique in that it can modify itself unpredictably, surviving as it has for centuries. Our current knowledge of this virus and the human viral immune defense mechanisms has led to the creation of select treatment options and vaccines. However, as good as these options can be, they do not always work. For instance, last year’s influenza serum was largely ineffective due to the virus mutating beyond the detection of the antibodies elicited by the vaccination.  This year’s flu shot, thankfully, is considered to be a better match for the influenza virus, but it does leave doubt in many people’s minds as to the overall effectiveness of continuous flu vaccinations. Nevertheless, vaccinations are considered the best defense we have right now against the flu, so it may be wise to learn more about them and the current spread of the influenza virus in your community before you decide to let nature take its course.
With today’s advancing technologies, we are so close to finding better treatments for many viral-related diseases and influenza could be the next big breakthrough. To get there, more research is needed and the study of epigenetics will undoubtedly further our understanding of the influenza virus and the mechanisms that regulate host-pathogen gene expression in all viral infections. Researchers are already saying that a universal flu vaccine may be just around the corner.  As for now, it’s probably best to get your annual flu shot and avoid sick people. Of course, getting enough sleep and eating healthy to boost your immune system might work, too.
- Galvan S.C., García Carrancá A., Song J., Recillas-Targa F. (2015). Epigenetics and animal virus infections. Front Genet., 6: 48.
- Wikipedia. Influenza A virus subtype H1N1. Web.
- Centers for Disease Control and Prevention (CDC). How the Flu Virus Can Change: “Drift” and “Shift”. Web.
- Marazzi, I., Ho J.S., Kim J., Manicassamy B., Dewell S., Albrecht RA., Seibert C.W., Schaefer U., Jeffrey K.L., Prinjha R.K., Lee K., García-Sastre A., Roeder R.G., Tarakhovsky A. (2012). Suppression of the antiviral response by an influenza histone mimic. Nature. 483(7390): 428–433.
- Ou J-hJ. (2014). Virus Control Goes Epigenetic. PLoS Pathog. 10(9): e1004370.
- Gack, M.U., Albrecht R.A., Urano T., Inn K.S., Huang I.C., Carnero E., Farzan M., Inoue S., Jung J.U., García-Sastre A. (2009). Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 8;5(5):439-49. J. Virol. 88 (11) 6128-6136.
- Centers for Disease Control and Prevention (CDC). Seasonal Influenza Q&A. Web.
- Goritzka, M., Durant, L.R., Pereira, C., Openshaw. P.J.M., Johansson, C. (2014). Alpha/Beta Interferon Receptor Signaling Amplifies Early Proinflammatory Cytokine Production in the Lung during Respiratory Syncytial Virus Infection.
- Fang, J., Hao, Q., Liu, L., Li, Y., Wu, J., Huo, X., Zhu, Y. (2012). Epigenetic Changes Mediated by microRNA miR29 Activate Cyclooxygenase 2 and Lambda-1 Interferon Production during Viral Infection. J Virol: 86(2): 1010–1020.
- Mukherjee, S., Vipat, V.C., Chakrabarti, A.K. (2013). Infection with influenza A viruses causes changes in promoter DNA methylation of inflammatory genes. Influenza Other Respir Viruses: 7(6), 979–986.
- Mitch Leslie (2015). Why last year’s flu vaccine didn’t work so well. Sciencemag.org.
- Satran, J. (2015). Scientists Take Huge Step Toward Universal Flu Vaccine. The Huffington Post. Web.
- Click to share on Tumblr (Opens in new window)
- Click to share on Pocket (Opens in new window)
- Click to print (Opens in new window)
- Click to email this to a friend (Opens in new window)
- Click to share on StumbleUpon (Opens in new window)
- Click to share on Reddit (Opens in new window)
- Click to share on WhatsApp (Opens in new window)
- Click to share on Telegram (Opens in new window)
- Click to share on Facebook (Opens in new window)
- Click to share on Twitter (Opens in new window)
- Click to share on Pinterest (Opens in new window)
- Click to share on Skype (Opens in new window)