Literature Overview: Influenza (H1N1)

Reflection Blog #3

Influenza, though only first making a prominent appearance in the scientific literature around the early nineteenth century, has plagued humanity since at least the 1500s. 5 Given this, its scientific study extends far back, easily preceding identification of the first virus, and resulting in a somewhat overwhelming abundance of literature. I have chosen to focus on H1N1 for this project, though it is common that scientific understanding of the H1N1 subtype is informed by studies in other influenza strains. Presented below are four core themes, and two less prominent, supplementary themes*, which describe and navigate the nature of biochemical research in H1N1 and influenza available.

Clinical characterization*

Though not the focus of this (biochemical) project, clinical characterization set an important precedent to the molecular study of the influenza virus. Influenza is thought to have first appeared in the late 1500’s, though possibly earlier, and was responsible for many prominent epidemics prior to its more scientific study in the early nineteenth century.1 Much available literature through the nineteenth and early twentieth century appears to be focused on characterizing the clinical presentation of influenza (identifying symptoms), and distinguishing it from other infectious conditions.

While this project will focus much less on this theme than the others listed below, it is worthy of mention as an important historical context for the more molecular literature that follows. 

Identification of the causative agent 

Given the prominence of influenza in human history – ranging from seasonal outbreaks to devastating pandemics such as the 1918 H1N1 flu, it is not surprising that, particularly in the late nineteenth century through the early twentieth century, there is an abundance of literature attempting to elucidate the causative cause of the disease. Through clinical observation, it was clear that the disease was infectious by nature, but even once more microbial-based studies took place, there was some debate about whether the causative agent was bacterial or viral (the bacteria identified turned out to be a common co-infection4). Post identification of the virus itself (1933), this becomes less prominent in the literature, though more recent work has focused on classifying viral subtypes and protein components, leading to the “Cellular and Structural Basis of Infection” theme discussed below.

Major scientific innovations contributing to this theme (and some interesting historical notes on the origin of these findings): 

  • 1800s-1918 – Pfiefer’s bacteria (“bacillus of influenza”) is identified as causative agent 2
    Pfiefer identified a bacillus bacteria in the respiratory tract of patients presenting with influenza-like symptoms. This was thought to be the causative agent for some time, before subsequent work suggested it may be viral. Some early attempts at vaccine development were actually bacterial. 
  • 1918 – Gibson and Connor demonstrate the influenza from the 1918 outbreak is caused by a filterable virus 3
    Gibson and Connor demonstrate that the causative agent for influenza is a filterable virus during the 1918 pandemic, appearing to shift the literature away from Pfieffer’s bacteria. 
  • 1933 – The influenza virus is isolated 4

Cellular and structural basis of infection

As molecular and biochemical sciences evolve as a field, a new theme emerges in the literature focusing on understanding influenza infection from this perspective. This likely starts with antigenic characterization of the hemagglutinin and neuraminidase surface proteins typically used to categorize influenza strains into an H#N# subtype, but develops into immunological, biochemical, and genetic study of influenza pathogenesis and function. This type of research still thrives today, with an incredible bank of molecular interactions identified – including interactions with the host cell immune pathways triggered by infection. Understanding the molecular basis for infection and host immune response is essential to creating novel drug therapies, so it is not surprising that this is a focus in the literature. 

Major scientific innovations contributing to this theme:

  • 1941-42 – George K. Hirst suggests existence of the hemagglutinin protein 6
    Named for the observation that red blood cells agglutinate in the presence of the virus 
  • 1943 – Early chemical characterization of influenza as a lipoprotein complex 7
  • 1950s – Alfred Gottschalk identifies and characterizes the hemagglutinin and neuraminidase proteins7 
  • 1990s-present – Extensive mapping of infection mechanism and host immune pathways 5,12 

Genetic study of influenza

While structural protein studies of influenza preceded genetic study, there is also an abundance of literature examining the virus from a genetic lens. This is primarily focused on understanding the viral genome components, and their roles in infection. Like all viruses, influenza contains the genetic material necessary to build its protein components, but must exploit the machinery of a host cell during infection to synthesize new viruses.5 There is also a large interest in the virus’s ability to genetically recombine, as influenza is exceptionally good at this, and it is one of the major barriers to vaccine development. Potential for mutation, which may increase the virulence of the pathogen is also of interest in understanding influenza.5

Major scientific innovations contributing to this theme:

  • 1952 – Demonstrated that influenza can genetically recombine 8
  • 1976-1977 – Mapping of the influenza genome 9,10,11
    Identifies genes encoding the primary viral proteins necessary for infection and viral assembly 
  • 1990s-present – Extensive mapping of infection mechanism and host immune pathways 5,12
    Including genetics-based studies

Treatment, Prevention, & Transmission 

Because influenza is often highly virulent, particularly H1N1, and can be extremely dangerous to at-risk populations,6 treatment and prevention of disease is one of the most prominent focuses of influenza study. This includes vaccine development, antiviral pharmaceuticals, and public health efforts to prevent spread of disease (less relevant to this project). As discussed above, the frequent genetic drift of influenza viruses makes vaccine development difficult. Currently, seasonal vaccines can provide protection from the most common strains in a given year, but there is interest in creating a “universal vaccine” which could provide protection from all strains in the future.5 A variety of antiviral drugs have also been developed.13 Interest in potential treatments begins with interest in the disease itself, but biochemical and pharmaceutical efforts to develop novel treatments is still prominent today. As with bacterial infections, this field also faces modern issues with drug resistance in viral strains.5

In accordance with interest in prevention, there is also a large focus throughout the literature on mechanisms of transmission. Influenza viruses can come from a variety of animals, though the H1N1 subtype is typically found in pigs, and mechanisms of both animal-human and human-human transmission are of prominent interest in prevention of potential outbreaks.

Major scientific innovations contributing to this theme:

  • 1918 – Early attempts at vaccine development, but targeting the “bacillus of influenza,” rather than the virus itself
  • 1933 – Serum from recovered animal is shown to protect others from influenza infection 4 
  • 1945 – First influenza vaccine developed and implemented for civilian inoculation 5
  • 1990 – Reverse genetics technologies to generate desired recombinant influenza enhances vaccine development efforts 5
  • Present day – efforts into developing a universal influenza vaccine are underway5

Examining genetic factors & predispositions* 

An emerging theme in the literature of more recent interest is the role that genetic factors may play in susceptibility to severe influenza infection. Factors such as age and pre-existing health conditions have been known to increase susceptibility for some time,5 but that idea that there may be other genetic factors implicated in susceptibility is relatively new. Mutations identified thus far typically interfere with the canonical host response.5 This area is currently poorly understood, but I suspect that it will be of interesting focus in the biochemical and genetic literature on influenza moving forward.

Major scientific innovations contributing to this theme

  • 2010s – Identification of IFITM3 and IRF7 mutations, encoding interferon pathway components, as implicated in susceptibility to severe influenza infection 

I believe these themes will integrate well with the Defining the Disease Mastery Assignment and other components of the capstone project, as they focus on answering many of the major questions about influenza such as how it spreads, how it causes disease, possible treatments, and what leads to susceptibility in certain individuals. Additionally, the core themes outlined above are largely focused in biochemical/molecular study.

Works Cited 

  1. Brief History of the Influenza Virus http://www.mypediatriccenter.com/brief-history-influenza-virus/. (Accessed 27 March 2020).
  2. Robertson, W.F. Influenza: Its Cause and Prevention. Br Med J. 1918, 2(3025):680-681.
  3. Gibson, H.G., and Connor, J.I. A filterable virus as the cause of the early stage of the present epidemic influenza. Br Med J. 1918, 2(3024):645-646.
  4. Smith, W., Andrewes, C.H., and Laidlaw, P.P. [Reviewed] Timbury, M.C. A Virus obtained from influenza Patients. Reviews in Medical Virology. 1995*, 5:187-191 
  5. 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.
  6. Henry, R. and Frederick, M.A. Etymologia: Hemagglutinin and Neuraminidase. 2018 Emerg Infec Dis. 24(10), 1849. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154157/
  7. Taylor, A.R., Sharp, D.G., McLean, I.W., Beard, D., Beard, J.W., Dingle, J.H., and Feller, E. Jr. Purification and Character of the Swine Influenza Virus. Science. 1943, 98(2557):587-89
  8. Burnet, F.M. and Lind, P.E. A genetic approach to variation in influenza viruses; recombination of characters between the influenza virus A strain NWS. and strains of different serological types. 1951 J Gen Microbiol. 5(1):67-82. https://www.ncbi.nlm.nih.gov/pubmed/14824472
  9. Palese, P., and Schulman J.L. Mapping of the influenza virus genome: identification of the hemagglutinin and the neuraminidase genes. Proc Natl Acad Sci USA. 1976, 73(6):2142-46.
  10. Palese, P., Ritchey, M.B., and Schulman J.L. Mapping of the influenza virus genome II: identification of the P1, P2, and P3 genes. Proc Natl Acad Sci USA. 1977, 76(1):114-121
  11. Ritchey, M.B., Palese, P., and Schulman J.L. Mapping of the influenza virus genome III: identification of genes coding for nucleoprotein, membrane protein, and nonstructural protein. Journal of Virology. 1976, 20(1):307-313
  12. KEGG. Influenza A pathway.  https://www.kegg.jp/kegg-bin/show_pathway?hsa05164+H00398 
  13. CDC. Influenza. https://www.cdc.gov/flu/ (Accessed 26 March 2020).
  14. Everitt, A.R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012, 484:519-23.

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