Capstone Project: Influenza

Influenza A, SUbtype H1n1

This post is intended to be an overview, but much more detailed information can be found from the links at the bottom of this page. Please feel free to leave a question or comment!


Influenza, or the flu, is a common and highly contagious viral infection. While severity of infection varies year-to-year, the CDC estimates that there are between 9 million and 45 million cases of influenza in the United States alone each year, leading to 12,000-61,000 deaths. Globally, the WHO estimates there are roughly 1 billion cases annually.

Reports of influenza-like illness date back to 410 B.C. The most notable historic influenza, though, is that of 1918 – an H1N1 influenza virus which killed roughly 50 million people – approximately 3% of the world population at the time, and greater than the death toll of the First World War.

If the timeline does not load properly, reload the page. Click here to view summary timeline (featured image).

Symptoms

Symptoms of mild influenza infection include:

    • Fever/Chills
    • Headache
    • Cough
    • Sore throat
    • Congestion
    • Fatigue 

Influenza infection can become much more serious in individuals with pre-existing health conditions or weakened immune systems. One of the most common complications of influenza infection is pneumonia, which can lead to acute respiratory distress, and often results in hospitalization.

What exactly is the flu?

Viruses are submicroscopic pathogens composed of genetic material and a protein/lipid coat. Our genetic material is made up of DNA, or deoxyribonucleic acid, but the influenza virus carries something slightly different, called RNA (ribonucleic acid). These structures serve the same purpose of encoding the information to build necessary proteins. However, unlike our cells, viruses don’t have the cellular machinery needed to build those proteins. Instead, they must infect a host cell and recruit its machinery to synthesize new copies.

There are three  types of influenza viruses which infect humans – A, B, and C – but influenza A is the most common. Influenza A viruses can be further classified into subtypes based on the proteins found on their surface, hemagglutinin (HA) and neuraminidase (NA), which are what the H#N# nomenclature refers to. For example, the 2009 influenza pandemic was Influenza type A, subtype H1N1, meaning that it had type 1 hemagglutinin and neuraminidase surface proteins.

A visual representation of different influenza subtypes

The virus gains access to the host cell, typically in the respiratory tract, with the hemagglutinin surface protein, which binds a chemical structure embedded in the host cell membrane called sialic acid. This binding allows the virus to enter the cell and release its RNA segments inside, which are transported to the nucleus for processing. RNA acts like a code that provides the cell with instructions for building proteins, but the RNA carried by the influenza virus is negative-sense. This means that it must be converted to the complementary positive-sense RNA (now called messenger RNA or mRNA) before the cell can interpret it. This conversion is facilitated by an RNA polymerase enzyme. The original, negative-sense RNA is also copied to become the genetic material of the newly synthesized viruses.

The influenza virus lifecycle. Hemagglutinin (HA); Neuraminidase (NA), messenger RNA (mRNA).

mRNA leaves the nucleus, and organelles called ribosomes convert it into functional proteins. These proteins are combined with the copies of the original RNA material to form new virus particles, which fuse with the cell membrane to exit the cell. The virus is released when the neuraminidase surface protein clips its linkage to a sialic acid on the host cell surface, and the freed virus can go on to infect other host cells.

This process takes a toll on the host cell, as the majority of resources are put towards viral production. Additionally, presence of the virus in the cell activates the immune system, preparing the body to fight the infection. Intracellular immune proteins recognize various unique viral components, such as its RNA, and produce signaling molecules, such as interferons and interleukins, designed to restrict viral replication. The effects of this signaling protect the body, but also lead to many of the symptoms typically associated with influenza, such as fever, inflammation, and irritation of the respiratory tract. 

Treatment and Prevention

While there are vaccines and antiviral treatments available, one of the most pharmacologically challenging characteristics of the influenza virus is its prominent ability to accrue mutations and recombine. Mutations occur frequently, and the segmented RNA can recombine if two different influenza subtypes infect the same cell. 

These events make it difficult to create effective vaccines because the antibodies an individual makes against a strain in the vaccine may not be effective if they are exposed to a mutated or recombinant strain later on, which is why the influenza vaccine is recommended annually. Despite this challenge, vaccination is still the best way to prevent and lessen the severity of influenza infection. These issues have prompted prominent interest in the possibility of a universal influenza vaccine, which would theoretically target a well conserved portion of the virus, though, this project has proven difficult. As the research progresses, though, this will hopefully become a reality in the future. 

For more information on current and future potentially universal influenza vaccines, check out this video from a lab at Mount Sinai.

You can learn more by exploring my Capstone Project Pages: 

  1. Clinical Characterization 
  2. Identification and Characterization of the Infectious Agent 
  3. Cellular & Molecular Basis of Infection 
  4. Host Immunity & Preserving the Healthy State 
  5. Treatment, Prevention, & Transmission 
  6. Examining Genetic Factors & Predispositions 

Or, click below to view my Capstone Project Landing Page. 

References

Main Text

  1. CDC. Disease Burden of Influenza. (Accessed April 21, 2020) https://www.cdc.gov/flu/about/burden/index.html
  2. WHO. Global Influenza Strategy 2019-2030. (Accessed April 21, 2020) https://www.who.int/influenza/Global_Influenza_Strategy_2019_2030_Summary_English.pdf?ua=1
  3. History. Influenza. 2020 (Accessed April 22, 2020). https://www.history.com/topics/inventions/flu
  4. CDC. Types of Influenza Viruses. (Accessed March 12, 2020) https://www.cdc.gov/flu/about/viruses/types.html
  5. Eisenstein, M. Towards a universal flu vaccine. Nature Outlook. 2019 https://www.nature.com/articles/d41586-019-02751-w
  6. Chen, X.; Liu, S.; Goraya, M.U.; Maarouf, M.; Huang, S.; and Chen, J. Host Immune Response to Influenza A Virus Infection. Front Immunol. 2018, 9: 320. https://dx.doi.org/10.3389%2Ffimmu.2018.00320
  7. Krammer, F.; Smith, G. J. D.; Fouchier, R. A. M.; Peiris, M.; Kedzierska, K.; Doherty, P. C.; Palese, P.; Shaw, M. L.; Treanor, J.; Webster, R. G.; et al. Influenza. Nat. Rev. Dis. Primer 2018, 4 (1), 1–21. https://doi.org/10.1038/s41572-018-0002-y
  8. Dou, D.; Revol, R.; Ostbye, H.; Wang, H.; and Daniels, R. Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement. Front Immunol. 2018, 9: 1581. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062596

Note: Images in main text are not linked to direct sources because they are original content.

Timeline & Timeline Images

  1. CDC. Influenza (Flu) (Accessed Apr 14, 2020) https://www.cdc.gov/flu/
  2. CDC. 1918 Commemoration Historical Images [Image] (Accessed Apr 21, 2020). https://www.cdc.gov/flu/pandemic-resources/1918-commemoration/historical-images.htm#
  3. Wikipedia. Richard Pfeiffer [Image] (Accessed Apr 21, 2020). https://en.wikipedia.org/wiki/Richard_Friedrich_Johannes_Pfeiffer
  4. Machemer, T. How a few sick tobacco plants led scientists to unravel the truth about viruses. Smithsonian, 2020. (Accessed Apr 21, 2020). https://www.smithsonianmag.com/science-nature/what-are-viruses-history-tobacco-mosaic-disease-180974480/
  5. Huston History: The flu pandemic Huston faced 100 years ago [Image] (Accessed Apr 21, 2020). https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.click2houston.com%2Fhouston-life%2F2020%2F03%2F24%2Fhouston-history-the-flu-pandemic-houston-faced-100-years-ago%2F&psig=AOvVaw1PSbrMWpqo90qUfsjplXiJ&ust=1587691892211000&source=images&cd=vfe&ved=0CA0QjhxqFwoTCNC0rrSz_egCFQAAAAAdAAAAABAD
  6. Science Photo. Influenza A Virus, TEM [Image]. (Accessed Apr 21, 2020). https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.sciencephoto.com%2Fmedia%2F864731%2Fview%2Finfluenza-a-virus-tem&psig=AOvVaw04ffg2O0AbH9Fg2K9ISnAA&ust=1587692564403000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCID79e61_egCFQAAAAAdAAAAABAD
  7. Virology Blog. The neuraminidase of the influenza virus [Image]. 2013. (Accessed Apr 21, 2020). https://www.virology.ws/2013/11/05/the-neuraminidase-of-influenza-virus/
  8. Drugs.com. Amantadine Syrup [Image] (Accessed Apr 21, 2020). https://www.drugs.com/pro/amantadine-syrup.html
  9. Tao, Y.J.; and Zheng, W. Visualizing the Influenza Genome (Figure 1) [Image]. Science. 2012, 338(6114): 1545-1546. https://science-sciencemag-org.muhlenberg.idm.oclc.org/content/338/6114/1545
  10. Moisse, K. Young Swine Flu Survivor Gets Kidney from Mom. ABC News. 2013 (Accessed Apr 21, 2020). https://abcnews.go.com/Health/young-swine-flu-survivor-kidney-mom/story?id=19826287

8 Replies to “Capstone Project: Influenza”

  1. Is the sialic acid to be found on most cells in the human body? Or is it found mostly attached to cells in the respiratory system which is why that is the main target of the virus?

    Is it this way with most viruses? They have hooks which catch on to only certain chemicals which are to be found only on cells of this type or that type so that the infect only this subsystem, or that subsystem?

    Some of our worst pandemics come from zoonotic transfer. What are these viruses doing in hosts that they do not harm? Are they floating around loose in the animal host but not attaching to cells and reproducing? How long can they last that way?

  2. Thanks for your comment!

    Sialic acids are abundant in the body, and play a role in a wide range of physiological processes (not only infection). They can be found in cell surface sugars on all vertebrate cell types, as well as attached to proteins within the cell. Sialic acids play a role in the infection and disease of pathogens targeting body systems entirely separate from the respiratory tract, such as meningitis (nervous system) and peptic ulcer disease (digestive system). However, different types of sialic acids exist. Human influenza A viruses target a sialic acid with a specific type of linkage. These specific chemical structures, in addition to the route of exposure to the virus, may be what confine the virus to infection of the respiratory tract. In other species, where the influenza virus has other modes of transmission, it can also infect the intestinal tract, for example.

    All viruses require some mode of entry to a cell – so in a certain sense what you are saying is correct, from what I understand. However, the “receptors” which the virus binds on the cell surface may not always be a small structure like sialic acid. SARS-CoV-2, for example, binds the ACE2 receptor for cell entry. ACE2 is an enzyme which is much larger and more complex than the sialic acids bound by influenza.

    It is true that zoonotic transfer plays a significant role in human disease. In some cases, such as with malaria and mosquitos, the pathogen can live inside the vector without causing harm. The parasite which causes malaria can live inside the mosquito without causing harm, for example, because of a special characteristics of the mosquito’s hemolymph (similar to blood) (read more: https://cosmosmagazine.com/biology/why-mosquitoes-don-t-die-from-malaria). However, influenza is often capable of causing disease in its animal host. In pigs for example, it causes a pneumonia-like illness very similar to its symptoms in humans. Influenza has also been known to cause disease in domestic dogs and cats.

  3. Hey Miranda!

    One of the things I was particularly intrigued by on this page was how much earlier a vaccine for the influenza A virus was developed than an effective antiviral drug. Does this mean that developing a drug to treat viral infection is more difficult that making a vaccine to prevent it? If so, why is that? Thank you!

    1. Hi Isabella!

      Thank you so much for your comment, that is a great point! This may be more a matter of history than of difficulty in creating one treatment or the other. Vaccination (in some capacity) dates back to the late 1700s, while antiviral treatments were not available (for any virus) until the 1960s. The development of both vaccines and antiviral treatments which are safe and effective are complex processes. Antiviral treatments are generally regarded as more difficult to develop than antibiotics, which is evidenced by their relative abundance. Unlike antiviral medications, which are typically administered to patients with confirmed infections, vaccines are given to the healthy, meaning they may face slightly higher safety and side-effect standards. Today, these two strategies would likely develop on a much more similar, though unfortunately still slow, timeline (as we are seeing in the COVID-19 response).

  4. Hello, great information on here. I love the graphics and you have organized this so well; it was so easy to follow. I am wondering if there is any meaning behind the fact that you indicated in your diagram that neuroaminidase is built once for every six hemagglutinin proteins within one cell. Also, what are these surface proteins imitating in the human body? Love this!!

    1. Hi Becca!

      Thank you! I did not intend for the diagram to indicate a relative abundance of hemagglutinin and neuraminidase proteins, but I believe that the two proteins are expressed in relatively similar abundance on the viral surface. These proteins mediate the interaction between the virus and host cell by binding cell surface chemical structures upon viral entry and releasing the virus from such structures during viral budding, respectively.

    1. Hey Celeste, thanks for your comment!

      Antibodies bind viral or bacterial proteins with extreme specificity. This specificity is what allows your immune system to recognize pathogens accurately and fight infection. However, when the region an antibody is specific to changes due to a mutation, the virus may not be recognized, precluding a sufficient immune response.

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