The Coming Influenza Pandemic Part II

In Part I, I discussed the deadly flu pandemic of 1918-1919 and started to explain the biology and morphology of Influenza. In Part II, we will look more at the genetics and morphology of Influenza as well as its etiology (how the disease progresses in humans) and its ecology.

From Wikipedia

 The first step to any viral infection involves adherence to the host cell. Influenza does this by using its hemagglutinin to bind to sialic acid sugars on surface of epithelial cells in the nose, throat and lungs of mammals or intestine of birds.⁷ Host proteases (enzymes that break down protein) cleave the hemagglutinins, leading to endocytosis (engulfment) into the host cell.⁷ The low pH of the endosome (a vesicle made of host membrane surrounding the virus) causes the viral core to dissemble, releasing its RNA. Viral core proteins enter the host nucleus, forcing host cells to make positive-sense viral RNA (vRNA).⁷ The host then translates the viral genes and assembles new influenza virions, which escape the host cell with the aid of neuraminidase.

From Wikipedia

 Virulent strains have hemagglutinins that can be cleaved by proteases found throughout the body, especially deep in the lungs, where an infection has much more serious consequences than infections higher up in the respiratory tract.⁷ Mild strains have hemagglutinins that can only be cleaved by proteases found in the trachea, producing less severe symptoms.⁷ Strains such as H5N1, which have the ability to infect numerous different species, have hemagglutinins that can be cleaved by proteases from a variety of hosts (e.g., duck, chicken, pig, human). While avian hemagglutinins typically can only be cleaved by proteases found in the avian gut, H5N1 has the ability to infect the avian gut, as well as the mammalian respiratory tract, allowing it to infect a variety of avian and mammalian species.⁷

Influenza is usually acquired by inhalation or ingestion, but can also be transmitted through the eyes.^13(p582) Influenza is stable on surfaces and can be picked up from tables, doorknobs, shared food and utensils. It has an incubation period of 1-2 days and is highly infectious even before symptoms appear. Influenza destroys the ciliated cells of the respiratory tract which are important for sweeping away dust and germs.⁷ Damage to these cells increases susceptibility to secondary infections by bacteria that cause pneumonia (e.g., Haemophilus influenza, Staphylococcus aureus and Streptococcus pneumonia).^3(p22)

Acute strains also may kill directly through pulmonary edema, hemorrhage, rapid destruction of the respiratory epithelium⁵ or through a cytokine storm (a potentially lethal immune response that involves the sudden release of over one hundred inflammatory regulators).⁸ Both the 1918 pandemic H1N1 strain, and the current, highly pathogenic avian strain, H5N1, are thought to be able to kill through a cytokine storm.⁸

 

The influenza genome contains 7-8 segments of single-stranded, negative sense RNA, for a total of approximately 10,000 nucleotide bases.^7,13 The high error rate of RNA Polymerase (1 error every 10,000 nucleotides) leads to an average of one mutation each time the genome is replicated.⁷ In other words, every time a host cell lyses and releases new virions, the new virions have a slightly different genotype than their parents. This mutation rate, while fast compared to DNA-based genomes, is still slow enough that people may retain some immunity over the course of two or three flu seasons because the newer strains often retain some of the surface antigens of their parents.^7,13(p583) This gradual evolution of the virus is known as antigenic drift.^7,13

Antigenic shift is a much more sudden and dramatic change in the surface antigens that results from genetic reassortment between different strains. Such gene swapping can occur when a host is coinfected with two or more different subtypes of influenza.^3(p16)

From Wikipedia

 The human immune system produces white blood cells called B lymphocytes.^13(p700-3) One type of B lymphocyte is the plasma cell, which produces proteins on its surface called antibodies. B plasma cells, like influenza, mutate very rapidly, resulting in thousands of different varieties, each with different antibodies. An antibody with a complementary shape to an antigen can bind to it, setting off a cascade of immune responses that help to destroy the pathogen carrying that antigen. This is called a primary response and occurs whenever we are exposed to a new germ to which we lack immunity. Another type of immune cell is also produced, called memory B cells, whose function is to retain the DNA for a particular antibody. If we are later re-infected with the same germ, the memory cells rapidly kick into action to destroy the pathogen before it makes us sick. This is called a secondary response. Vaccines function by training our immune systems to make B cells for a particular illness so that we have a secondary response and avoid illness if we are ever exposed to that disease. Vaccines by-pass the initial phase of immune response where you first get sick by using killed or attenuated germs or antigens that do not cause disease, but still stimulate an immune response.

Antigenic drift is a gradual change in the surface antigens of influenza, specifically hemagglutinin and neuraminidase. Antigenic drift causes seasonal influenza to change slightly each year. This is why a single flu vaccine does not protect us for life, unlike many other vaccines (e.g., smallpox, chickenpox, and measles). New flu vaccines must be reformulated each year by carefully monitoring the various recent and novel strains that scientists have observed. Because antigenic drift is relatively slow and leads to only modest changes in the topography of the influenza virus, making effective seasonal flu vaccine is fairly easy and usually pretty successful.⁷

Antigenic shift, in contrast, because it involves gene swapping between different strains, can lead to sudden and dramatic changes in the surface topography of the virus. It can also lead to significant changes to the internal proteins, some of which influence virulence. Because it can occur suddenly, antigenic shift can make it difficult to produce an effective vaccine quickly enough to protect the public.^3,7,13

Many people routinely forego the flu vaccine because they do not see the point. Seasonal flu does not usually kill many healthy adults and morbidity declines with age. Adults have already been exposed to several strains in their lifetimes and have developed immunity to many of these. Further, as far as scientists are aware, highly pathogenic strains, such as the H5N1 avian flu, do not yet have the ability to easily infect humans. So, why should anyone worry about deadly flu pandemics?

Check tomorrow for Part III, where I will discuss the other deadly pandemics of the past century and the development of novel Highly Pathogenic Avian Influenzas (HPAI) that could evolve into the next deadly pandemic.

References

1. AVERT, 2009, AVERTing AIDS website, October 28, 2009: http://www.avert.org/worldstats.htm
2. Bartlett, Donald L.,  and James B. Steele, 2004, “The Health of Nations,” New York Times, Oct 24,
3. Davis, Mike, 2005, The Monster at Our Door, The New Press, New York
4. Enserink, Martin, 2004, Science, 306, Dec ember 17, 2004
5. Kash, John C., Tumpey, Terrence M., Proll, Sean C., Carter, Victoria, Perwitasari, Olivia, Thomas, Matthew J., Basler, Christopher F., Palese, Peter, Taubenberger, Jeffery K., García-Sastre, Adolfo, Swayne, David E., and Katze, Michael G., 2006, “Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus,” Nature. October 5; 2006, 443(7111): 578–581.
6. Soares, Christine, 2009, “Pandemic Payoff,” Scientific American, November, 2009, p19-20
7. Various Authors, 2009, “Influenza:,” from Wikipedia, accessed November 7, 2009, http://en.wikipedia.org/wiki/Influenza
8. Various Authors, 2009, “Cytokine Storm,” from Wikipedia, accessed November 7, 2009: http://en.wikipedia.org/wiki/Cytokine_storm
9. Various Authors, 2009, “Black Death,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/Black_Death
10. Various Authors, 2009, “1918 flu pandemic,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/1918_flu_pandemic
11. Various Authors, 2009, “Seasonal Influenza: the Disease,” Centers For Disease Control and Prevention website, accessed November 14, 2009: http://www.cdc.gov/flu/about/disease/
12. Wallace, Amy, 2009, “An Epidemic of Fear: How Panicked Parents Skipping Shots Endangers Us All,” Wired, October 19, 2009: http://www.wired.com/magazine/2009/10/ff_waronscience/
13. Willey, Joanne M., Sherwood, Linda M., and Woolverton, Christopher J.,  2009, Prescott’s Principles of Microbiology, New York, NY, McGraw Hill
14. Various Authors, 2009, “Pearl River Delta” from Wikipedia, accessed November 14, 2009: http://en.wikipedia.org/wiki/Pearl_River_Delta
15. Various Authors, 2009, “Cortisol,” from Wikipedia,  accessed November 16, 2009: http://en.wikipedia.org/wiki/Cortisol
16. California Newsreel, 2008, “Unnatural Causes,”  video.  Transcript accessed November 16, 2009: http://www.unnaturalcauses.org/assets/uploads/file/UC_Transcript_1.pdf
17. President’s Council of Advisors on Science and Technology, 2009, “Report to the President on U.S. Preparations for 2009-H1N1 Influenza,” August 7, 2009: http://www.whitehouse.gov/assets/documents/PCAST_H1N1_Report.pdf
18.  

Researchers Discover Antibody That Fights Multiple Flu Strains

In a major new discovery that could help prevent or treat influenza, researchers have identified an antibody that blocks the flu virus from entering its hosts’ cells and that can be used to cure already infected animals. The findings were reported in the most recent edition of the journal Nature.

Before a virus can make us sick, it must first adsorb (bind) to the surface of our cells and then get its DNA or RNA into our cells. Influenza A viruses use a protein on their surface called Hemagglutinin to attach to their hosts’ cells. Hemagglutinin is abbreviated “H” and the particular variety of Hemagglutinin forms part of the strain’s name (e.g., H1N1 or H5N1).  The “N” comes from an enzyme the virus produces called neuraminidase, which it uses to lyse (burst) its hosts’ cells in order to release newly formed virus particles.

The antibody discovered by lead author Ian Wilson (Scripps Research Institute) and colleagues at Scripps and Sea Lane Biotechnologies, binds to hemagglutinin thus preventing infection. This discovery may help in the development of more effective vaccines against the flu virus, which kills an average of 35,000 people per year in the U.S. alone. It could also help avert a deadly pandemic of avian influenza.

The research began by creating a library of antibodies from thousands of flu survivors from around the world by mining their bone marrow, which acts like a repository for all the antibodies they have ever made, the Bay Citizen reports. From this library, they were able to narrow their search to just the ones able to bind to influenza A. From this subset, they came upon the C05 antibody which protected cells growing in a Petri dish from influenza A infection. They also tried the experiment in vivo and found that C05 prevented mice from being infected. Furthermore, they discovered that mice already infected with a deadly strain of influenza were 100% cured when exposed to C05.

Perhaps the most exciting aspect of this research is that C05 binds to hemagglutinin, which is highly conserved genetically and used by many different strains to infect their hosts. Consequently, C05 is effective against several different varieties of influenza, including H1, H2, H3 and H9 strains. If C05 proves effective in preventing or treating human infections, this could be a major breakthrough, as we currently have little or no natural immunity to H9 strains and there is at least one highly pathogenic avian influenza H9 strain that has already wreaked havoc on some poultry flocks. This deadly strain could acquire person to person transmissibility through gene exchange with other flu viruses, as several H1 and H3 strains have already done, thus becoming the next deadly pandemic strain.