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.  

The Coming Influenza Pandemic (Part I)

Oakland, CA Hospital Ward 1918 (from Wikipedia)

 

 

 

 

As 2012-2013 shapes up to be a particularly bad year for seasonal flu, it is worth remembering that even during a good year, influenza kills an average of more than 30,000 Americans. More disturbingly, every 30-50 years the world sees a particularly deadly pandemic strain that kills hundreds of thousands or even millions of people.

When talking about plagues, pandemics and infectious holocausts, people generally think of modern day plagues, such as AIDS, which had killed 25 million people by 2008,² or ancient ones, like the Black Death, which killed an estimated 75-100 million people over the 50 years between 1348 and 1400.⁹  Many people don’t realize that the deadliest pandemic of all time was the Influenza pandemic of 1918-1919, which killed between 50 and 100 million people in just 2 years.^3(p25) 25 million people may have died in just the first 25 weeks of the pandemic.¹⁰ Over 15 million people died in India. 14% of Fiji and 20% of Western Samoa perished. In Europe, 250,000 British and 400,000 French died. In the U.S., five to six hundred thousand people died. Entire villages in Alaska were wiped out.¹⁰ Overall, morbidity rates were close to 50% and mortality rates ranged from 10 to 20%.^7,10

Because seasonal influenza returns each year and most adults have fairly robust immune responses due to repeated exposures to related influenza strains over their lifetimes, people tend to think of influenza as an unpleasant, but relatively harmless pest. The reality is that even the seasonal flu kills thirty to forty thousand Americans per year,^3(p22) while killing hundreds of thousands worldwide.⁷  Most of those who die are elderly, very young, immune-compromised, poor or malnourished.^3(p22)  However, a deadly strain, such as the 1918 influenza strain, can harm anyone due to its particular virulence and novelty, which leaves much of society lacking in any immunity.⁷

Spanish Flu (From Naval History & Heritage)

The name Spanish Flu is a misnomer, as the outbreak did not start in Spain, nor was Spain the hardest hit. The pandemic came in the midst of World War I. Most European countries, as well as the U.S., were censoring their media. Spain, being a neutral country, was one of the first to accurately report on this deadly new disease.¹⁰ 

Some scientists speculate that the pandemic started in a U.S. military barracks in Boston or Kansas in early 1918, from a mutated influenza virus that originated in China.¹⁰ From there it spread to Brest, France, with U.S. soldiers as the primary vectors. In the early stages of the outbreak, it resembled a typical flu season, with the elderly and sick being the hardest hit. By August, a second, deadlier wave of the virus hit Europe, the U.S. and Sierra Leone. Because the world was entrenched in a bloody war, many of those who were infected either stayed in the trenches, spreading the disease to their comrades and enemies, or were placed on transport trains and sent to field hospitals, where they spread the more virulent form of the disease to civilians.¹⁰

Electron Micrograph of 1918 Flu (from Wikipedia)

 

Influenza generally hits the very young and old the hardest, but it usually kills less than 1% of those who are infected.⁷ The 1918 pandemic was unusual in that it killed 10-20% of those infected, many of whom were young adults and otherwise healthy people. The elderly seemed to have had some degree of immunity. There had been another pandemic in 1889, known as the Russian flu. Many scientists believe that older people may have had some immunity to the 1918 strain through their exposure to this 1889 strain.¹⁰  Everyone else had little or no immunity; hence, the high morbidity rates.^3,10 

So where did this new strain come from? What made it so virulent? Why did pandemic influenza disappear for 29 years and then return in such a deadly and highly transmissible form? Could it happen again?

Image from Wikipedia

Influenza, is an RNA virus in the Orthomyxoviridae family.¹³ The enzymes that replicate RNA, unlike those that copy DNA, tend not to have the ability to proofread and repair mistakes. As a result, RNA viruses mutate rapidly, producing new forms that can evade our immune systems, leaving us vulnerable to infection. ^3(p15),7 Occasionally, these new forms are also particularly virulent, increasing the likelihood of death once we are infected. To make matters worse, influenza can readily swap genes with other influenza viruses. Thus, if a suitable vector, such as a pig, is infected with two different strains, a new strain can develop that is either particularly infectious or particularly virulent, or both, like the 1918 strain. 

 

Influenza A is endemic and usually harmless in birds, but it can cause serious illness in humans.^3,7 It is responsible for the majority of seasonal flu cases.^13(p582) Influenza A mutates rapidly and is readily able to swap genes with other influenza strains.^3,7 Some strains have the ability to infect multiple species. This is particularly dangerous and gives it high potential for creating deadly pandemics.^3,7 

Influenza B is endemic in humans, but rare in other species.⁷ It is usually very mild.¹³ It mutates 2-3 times more slowly than Influenza A.⁷  The combination of low mutation rate and low zoonotic potential makes Influenza B a very unlikely candidate for a deadly pandemic and, therefore, has very low pandemic potential.⁷ 

Influenza C can infect humans and some other mammals.⁷ It is usually mild and generally infects only children, though occasionally it does cause severe illness and epidemics. It is also considered to have low pandemic potential.^7,13

Influenza Morphology (from Wikipedia)

Hemagglutinin (HA) is a glycoprotein in the surface of the influenza virus that causes red blood cells to agglutinate.^3,7,13 It is the molecular key that allows the  influenza virus to enter the host cell. It is also considered an antigen, since it can stimulate the production of antibodies against it. Avian hemagglutinins can usually only infect avian gut cells; whereas human hemagglutinins can usually only unlock human respiratory cells. The species barrier between birds and humans is high (i.e., it is difficult for pure avian flu to mutate directly to a human flu). However, transmission between pigs and birds is relatively easy and the barrier between swine and humans is low. Hence, swine are an ideal mixing pot for mammalian and avian antigens.^{3, p17}

Neuraminidase is an enzyme that aids in cell lysis and the escape of virions from host cells. It is another antigen on the surface of the influenza virus.^3,7,13  Oseltamivir (trade name Tamiflu) is a neuraminidase inhibitor that functions by blocking the escape of new influenza virions from host cells, thus halting the progression and spread of the disease. It is one of the only drugs able to stop H5N1 and H1N1 influenza. ^3(p19),7

Influenza strains are named for the types of surface antigens in their envelopes. H1N1 has hemagglutinin 1 and neuraminidase 1, whereas H5N1 has hemagglutinin 5 and neuraminidase 1. There are 16 known HA antigens and 9 known NA antigens.⁷

^{This ends Part I of "The Coming Influenza Pandemic"}

^{Stay tuned for Part II, coming tomorrow} 

^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