H1NWHAT? Making Sense of the Virology of the Flu Matthew S

DefiningMomentsCanada.ca

H1NWHAT? Making Sense of the Virology of the Flu Matthew S. Miller

ust as the First World War was winding down in 1918, nature was set to release a scourge upon humanity Jcomparable in scale to the bubonic plague epidemics of the Middle Ages. Approximately 18 million people died and another 23 million were injured during the four years of the war (Mougel 2011).1 Yet over just two years, between 1918 and 1920, the “Spanish Flu” pandemic swept the entire planet, infecting about half a billion individuals, 50 to 100 million of whom would not survive (Johnson and Mueller 2002).2

In total, the pandemic caused the deaths of three to five percent of the global population at the time. Were a similar pandemic to occur today, the death toll would amount to the combined population of Canada and the USA – over 360 million people. Such extreme mortality rates are obviously a source of concern for health practitioners. Despite incredible advances in medicine since 1918, our ability to prevent or respond to flu pandemics remains almost unchanged.

Why does the flu continue to vex us while other devastating viruses of the past (e.g., smallpox, polio) have all but disappeared? To grasp the magnitude of this problem, one must understand the unique biology of the flu virus itself.

The “Spanish Flu” was caused by an influenza A virus (IAV), which comes in many forms. The type that caused the Spanish Flu was the “H1N1” virus, with the letters referring to two families of proteins -- hemagglutinin (H) and neuraminidase (N) -- found on the surface of the virus (Palese and Shaw 2007).3 These proteins coat the virus with spikes, helping it to enter and exit the cells in which it replicates. With 18 types of hemagglutinin and 11 of neuraminidase, there are 198 potential combinations that could adhere to IAVs (Tong et al. 2013).4

Only a few strains, however, have spread in the human population. That’s because IAV is actually not a human virus at all. Rather, it naturally infects aquatic birds, like ducks and geese, which are highly susceptible. However, over time, some forms of IAV `learned’ to infect almost all mammals – from dogs and cats to whales and sea lions (Ito and Kawaoka 2000).5 This is a unique property, since most viruses only infect a limited

1 Nadège Mougel, 2011. “World War I Casualties.” http://www.centre-robert-schuman.org/userfiles/files/REPERES – module 1-1-1 - explanatory notes – World War I casualties – EN.pdf. 2 Niall P A S Johnson and Juergen Mueller, 2002. “Updating the Accounts: Global Mortality of the 1918-1920 ‘Spanish’ influenza Pandemic.” Bulletin of the History of Medicine 76 (1): 105–15. http://www.ncbi.nlm.nih.gov/pubmed/11875246. 3 Peter Palese and Megan Shaw, 2007. “Orthomyxoviridae: The Viruses and Their Replication.” In Fields Virology, edited by David M Knipe, Diane E Griffin, Robert A Lamb, Stephen E Straus, Peter M Howley, Malcolm A Martin, and Bernard Roizman, 5th ed., 1647–90. Philadelphia: Lippincott Williams & Wilkins 4 Suxiang Tong, Xueyong Zhu, Yan Li, Mang Shi, Jing Zhang, Melissa Bourgeois, Hua Yang, et al., 2013. “New World Bats Harbor Diverse Influenza A Viruses.” Edited by Kanta Subbarao. PLoS Pathogens 9 (10). Public Library of Science: e1003657. doi:10.1371/journal. ppat.1003657. 5 Toshihiro Ito, and Yoshihiro Kawaoka, 2000. “Host-Range Barrier of Influenza A Viruses.” Veterinary Microbiology 74 (1–2). Elsevier: 71–75. doi:10.1016/S0378-1135(00)00167-X.

number of species.

The H and N proteins are also the parts of the virus recognized best by antibodies, those components of our immune systems that prevent infection. After an individual becomes infected with a virus for the first time, her immune system learns to recognize that specific virus and can then protect her from ever becoming infected with the same strain again. Our immune systems do this, in part, by producing antibodies, or defenders, that circulate in the blood, disarming these intruders if an individual is ever re-exposed. Unfortunately, antibodies released in response to a specific virus strain can’t recognize a different one (Ellebedy and Ahmed 2012).6 Consequently, when a virus disguises itself, it tricks the antibodies into letting their guard down, and an infection could again occur.

There are two ways IAVs disguise themselves from human immune systems. One, known as antigenic shift, will unleash wide-spread and lethal pandemics; the other, known as antigenic drift, produces far less deadly seasonal flu outbreaks.

Antigenic shift: Sometimes, the combination of H and N proteins on IAVs are capable of completely eluding the human immune response. Imagine a basic security system that is designed to spot and stop any approaching objects (the viruses) that are circular in shape. If the approaching objects are squares, however, this system won’t recognize them as threats, and lets them pass. A pandemic occurs when the IAV evolves so much than the human immune system can’t see it at all.

Antigenic drift: In other types of outbreaks, the IAVs haven’t changed as radically, and the immune system retains some ability to fight back. In the example above, the security system is programmed to recognize intruders as yellow circles, but also react to other incoming objects that look similar. In other words, if some of the approaching circles are orange, the security system can muster a partial response because it knows these other circles might be a problem.

Although the origin of the 1918 Spanish Flu virus remains uncertain, current evidence suggest it may have resulted from a mixing of human, swine and avian strains of IAV. The new virus – the square or perhaps even a hexagon, in the above example – tricked most individuals’ immune systems into not responding, thus allowing it to rapidly sweep through the global population.

After a pandemic occurs, the virus that caused it continues to circulate seasonally, sometimes for decades. It will mutate constantly, but those changes will also produce strains that human immune systems may partially recognize, as in the second example above. Our immune systems have some ability to ward off the virus, but not enough to completely prevent infection. This is why physicians and public health agencies promote the seasonal flu vaccine, which must also be re-engineered every year so it keeps up with mutations in the virus (Carrat and Flahault 2007).7

6 Ali H Ellebedy and Rafi Ahmed, 2012. “Re-Engaging Cross-Reactive Memory B Cells: The Influenza Puzzle.” Frontiers in Immunology 3 (January): 53. doi:10.3389/fimmu.2012.00053. 7 F. Carrat and A. Flahault, 2007. “Influenza Vaccine: The Challenge of Antigenic Drift.” Vaccine 25 (39–40). Elsevier: 6852–62. doi:10.1016/J.VACCINE.2007.07.027.

The upshot is that while seasonal flu does pose a serious health threat – causing 291,000 to 646,000 deaths globally each year (Iuliano et al. 2017) -- these figures pale in comparison to the mortality caused by the 1918 pandemic.8

Between 1918 and today, there have been a total of five IAV pandemics, the most recent of which was the 2009 H1N1 Swine Flu outbreak. Increasing urbanization, ever-expanding global travel and the lack of an effective prevention strategy leave the world extremely vulnerable to the potentially devastating effects of future IAV pandemics.

Thankfully, over the past decade, there has been an explosion in influenza virus research that has resulted in the development of promising new vaccine strategies and antiviral drugs, many of which are now in clinical trials. Only science can save us from the next flu pandemic. With vigilance and continued investment, we can ensure the 1918 Spanish Flu remains the most devasting influenza pandemic in human history.

REFERENCES

Carrat, F., and A. Flahault. 2007. “Influenza Vaccine: The Challenge of Antigenic Drift.” Vaccine 25 (39–40). Elsevier: 6852–62. doi:10.1016/J.VACCINE.2007.07.027.

Ellebedy, Ali H, and Rafi Ahmed. 2012. “Re-Engaging Cross-Reactive Memory B Cells: The Influenza Puzzle.” Frontiers in Immunology 3 (January): 53. doi:10.3389/fimmu.2012.00053.

Ito, Toshihiro, and Yoshihiro Kawaoka. 2000. “Host-Range Barrier of Influenza A Viruses.” Veterinary Microbiology 74 (1–2). Elsevier: 71–75. doi:10.1016/S0378-1135(00)00167-X.

Iuliano, A Danielle, Katherine M Roguski, Howard H Chang, David J Muscatello, Rakhee Palekar, Stefano Tempia, Cheryl Cohen, et al. 2017. “Estimates of Global Seasonal Influenza-Associated Respiratory Mortality: A Modelling Study.” The Lancet, December. doi:10.1016/S0140-6736(17)33293-2.

Johnson, Niall P A S, and Juergen Mueller. 2002. “Updating the Accounts: Global Mortality of the 1918-1920 ‘Spanish’ influenza Pandemic.” Bulletin of the History of Medicine 76 (1): 105–15. http://www.ncbi.nlm. nih.gov/pubmed/11875246.

Mougel, Nadège. 2011. “World War I Casualties.” http://www.centre-robert-schuman.org/userfiles/files/ REPERES – module 1-1-1 - explanatory notes – World War I casualties – EN.pdf.

Palese, Peter, and Megan Shaw. 2007. “Orthomyxoviridae: The Viruses and Their Replication.” In Fields Virology, edited by David M Knipe, Diane E Griffin, Robert A Lamb, Stephen E Straus, Peter M Howley, Malcolm A Martin, and Bernard Roizman, 5th ed., 1647–90. Philadelphia: Lippincott Williams & Wilkins.

8 A Danielle Iuliano, Katherine M Roguski, Howard H Chang, David J Muscatello, Rakhee Palekar, Stefano Tempia, Cheryl Cohen, et al., 2017. “Estimates of Global Seasonal Influenza-Associated Respiratory Mortality: A Modelling Study.” The Lancet, December. doi:10.1016/S0140-6736(17)33293-2.

Steel, John, and Anice C. Lowen. 2014. “Influenza A Virus Reassortment.” In , 377–401. Springer, Cham. doi:10.1007/82_2014_395.

Tong, Suxiang, Xueyong Zhu, Yan Li, Mang Shi, Jing Zhang, Melissa Bourgeois, Hua Yang, et al. 2013. “New World Bats Harbor Diverse Influenza A Viruses.” Edited by Kanta Subbarao. PLoS Pathogens 9 (10). Public Library of Science: e1003657. doi:10.1371/journal.ppat.1003657.