Humans Can Be Mixing Vessels for Viruses

By: Sarah Qiao

1/28/2020

On an April morning in 1997, a young three-year-old boy by the name of Lam Hoi-ka went to school in Hong Kong like many other children of his age. And, like many elementary schools around the world, his class received a clutch of chicks in a makeshift incubator. Like many of his classmates, Lam Hoi-ka picked up these chicks to play with them[1]. The world didn't know it yet, but Lam Hoi-ka was about to make history, uprooting principles of science that have served like the ten commandments in virology, biology, and epidemiology.

Lam Hoi-ka became ill on May 9, 1997. His illness increased in severity over the next week and half, resulting in multiple organ failure in quick succession before he passed away[2]. Doctors in Hong Kong realized they were dealing with something radically different from previous cases when tests revealed that the boy was suffering from flu, but a type that has never been seen in humans before. Understanding that he was dealing with a unique situation, Hong Kong's chief virologist, Dr. W. L. Lim, sent samples to laboratories around the world for help.

In the spring of 1997, there was a particularly dangerous strain of flu that had been ravaging Hong Kong's domestic poultry for months[3]. Thousands of chickens had been dying from a type of flu called H5N1. Chickens displayed horrifying symptoms, with their faces going “green or black”. Thick saliva came out of their mouths and birds had blood dripping out of their cloaca[4]. Frightening as the spring 1997 bird epidemic was, scientists were primarily concerned about what it could do to the poultry industry in China. Few scientists considered the possibility of humans contracting the virus because viruses simply did not jump from animals to humans in nature. Cross-species spread of viruses was unheard of because it simply has not happened before in recorded history. Bird cells are different from human cells, so how could a virus that infects bird cells infect human cells?

Dr. Lim's call for help launched a worldwide search for the origins of this mysterious flu that infected Lam Hoi-ka. Scientists from laboratories in the United States, the Netherlands, and the United Kingdom pitched in to identify the virus[5]. The Dutch team led by Jan de Jong from the Netherlands was the first to identify it; the virus that had sickened Lam Hoi-ka was the very same type that was killing the birds in Hong Kong, the H5N1 strain of avian flu.

The scientific community in that moment was shocked to its core. The foundations of what they believed, that cross-species spread was not possible, crumbled within days. What's further concerning was that it had happened naturally. Somewhere in Hong Kong, the virus was finding ways to adapt enough to infect humans outside of laboratories. Now the all-important question in the race to stop the virus from infecting more humans was: but where?

Twenty three years later, in 2020, the answer to where, how and under what conditions nonhuman viruses can mutate to infect humans remains elusive. Scientists generally believe that viruses evolve in third party animals that have close contact with humans (i.e. pigs), which serve as “mixing vessels” or incubators for non-human viruses to exchange and adapt their genome. Through these third party animals, nonhuman and human strains of virus can meet, evolve and exchange their genetic material in a way that could help them develop the tools to infect humans. However, it is clear that under the many different conditions a virus mutates, the consequences of these viral adaptations are vastly different; from causing a few localized infections to global pandemic. In the case of the 1997 Hong Kong outbreak, the virus had limited transmissibility. By the end of 1997, only 18 cases had been reported, with only 6 of them being fatal[6]. Contrasted with the 1918-1919 Spanish flu epidemic, which killed around 50 million people[7], the Hong Kong flu outbreak in 1997 had a very different outcome. Today, scientists have no clear answers to why this phenomenon happened.

Viruses evolve through two mechanisms. One way is by changing the letters in its genome, which allow it to selectively adapt to its environment over a period of time. This is what scientists call “antigenic drift”. The other way is to acquire and incorporate genetic fragments from other viruses. This is what scientists call “antigenic shift” or “reassortment”. The theory that pigs and/or other third-party animals serve as mixing vessels, relies on antigenic shifts, where nonhuman viruses can adapt the genetic information from human viruses so that they can develop ways to invade a normal human cell. This would require them to meet in the same environment, or host cell. Antigenic drift is considered less likely as a possibility for non-human viruses to evolve capabilities in infecting humans because it cannot even enter a human cell in the first place to develop any tools to further infect other human cells. That is why third-party mixing vessels have become the prevailing theory on how nonhuman viruses can jump to humans.

In the case of the third-party mixing vessels, a glaring problem remains with the theory applying to all cases of third party animal – human transmission of viruses: if nonhuman viruses evolve to become transmissible to humans in animals such as pigs, what accounts for the relatively mild outbreak of avian flu in 1997? Why is it that, despite it being evident that the avian flu jumped species to humans, only a few, select people were affected? In many people's retelling of Lam Hoi-ka's story, no account ever mentioned Lam Hoi-ka coming into contact with pigs or the like. Equally worrisome was the fact that no one could explain why none of Lam Hoi-ka's classmates fell ill. Research on where and under what circumstances human and nonhuman viruses can meet remains inconclusive. In fact, evidence that human influenza A viruses and avian influenza A viruses naturally prefer different types of cells (host cells) to infect, even amongst third-party animals[8]. This is in direct conflict with the foundation of the theory that, in order for the type of genetic resassortment that can help viruses jump species to occur, the viruses have to occupy the same host cell. Something is amiss.

Even now, the scientific community does not generally consider the hypothesis that humans, too, can serve as mixing vessels for nonhuman viruses. And until now, evidence of the naturally occurring mechanism by which a virus can infect a human cell has not been identified. However, an article written by Xueying Qiao provided evidence and concludes it is very likely that humans, not necessarily third-party animals, serve as a mixing vessel for human and nonhuman strains of viruses. In fact, he writes that humans may actually be the perfect host for nonhuman viruses to evolve pandemic-potential capabilities.

Mr. Qiao performs an experiment on the family of Cystoviridae, a bacteriaphage, to demonstrate this possibility. Bacteriaphages are viruses that infect bacteria, much like human viruses infect human cells. The Cystoviridae family has several strains of phage that infect different species of bacteria. Using two members of this family, Φ 6 and Φ 13, Mr. Qiao shows that these two different strains of virus that infect different “host” species can occupy the same host cell IF that host cell is a mutant, a variation of a normal host cell. For example, Φ 6 usually infects a bacteria called HB10Y that  Φ 13 cannot normally infect. However, HB10Y, the host, can produce a mutant host cell, LM2489, that both  Φ 6 and Φ 13 can infect at the same time. The resulting Φ 13 that “shifts” its genome with  Φ 6 can infect normal HB10Y cells[9]. In other words, Mr. Qiao has produced evidence that host cells can have variations that different species of viruses can exploit and infect. Not only can different strains of virus find their way into mutant host cells, they can further adapt within mutant host cells and become virulent to normal host cells that do not have mutations.

The implications from this experiment are enormous. It implies that human mutations can be an entry point for nonhuman viruses. With that established, it opens possibilities which explain why viral outbreaks can have very different consequences. Within a mutant human cell, viruses can choose to “drift” its genome so that it can adapt to its environment. The adapted virus can circulate and further infect mutated cells in an individual. Mr. Qiao cites evidence that the virus that infected Lam Hoi-ka was produced through antigenic drift, “varying one amino acid at position 92 of the NS1 protein molecule”[10]. The lethality of the virus is speculated to depend on where the virus infects this single individual and how many mutated cell hosts it can find. This could explain why Lam Hoi-ka was the only child affected in his classroom, even though he was not the only child to come in contact with the birds. It also could explain why, even though the avian flu in 1997 jumped from birds to humans, it was not as contagious between humans. The theory includes, not precludes, possibilities for viruses to develop capabilities that infect only few people (localized infections). These viruses with a drifted genome and limited transmissibility could further evolve to be able to infect normal human cells, developing pandemic potential.

The experiment also opens up the possibility that humans can provide the environment for nonhuman viruses to come into contact with human viruses. Once in mutant human host cells, nonhuman viruses are far more likely to encounter human strains of virus. Once they inhabit the same cell, the two strains of virus are more likely to exchange gene fragments, through antigenic shift, in a way that could be deadly for humans. Though it is not clear under what circumstances the viruses responsible for the 1957 “Asia Flu” and 1968 “Hong Kong Flu” mutated under, it is clear that both viruses had origins in human and avian strains of flu[11]. The resulting epidemics took millions of lives. In order to prevent from such future epidemics, the search for where the virus finds an entry point is key to combating viral contagions. Through Mr. Qiao's research and indirect evidence, we must consider humans as potential entry points as well.

In the past 5 years alone, the world has seen outbreaks of Ebola, Zika, MERS, and now COVID-19 which has affected millions of people worldwide[12]. In the case of COVID-19, approximately 780 million people are under lockdown[13] as Chinese authorities desperately try to stop 2019-nCoV from spreading further. These frightening numbers underpin how devastating the next pandemic could be. It is equally important to remember that these numbers do not tell the underlying story; of family members lost and/or affected by tragedy. Three-year-old Lam Hoi-ka was regretfully taken too soon because we do not have to tools yet to fight viruses, but he left behind an incredible legacy, a clue to scientists about how viruses behave. The race to stop the next tragedy is urgent, and human cell mutations might be the key in saving lives in the future.

 

[1] Arnold, Catharine. Pandemic 1918: Eyewitness Accounts from the Greatest Medical Holocaust in Modern History. (New York: St. Martins Press, 2018), 280.

[2] Ibid

[3] Ibid, 282.

[4] Ibid

[5] Sipress, Alan. The Fatal Strain: on the Trail of Avian Flu and the Coming Pandemic. Camberwell, Vic.: Penguin, 2011.

[6]  Arnold, Catharine. Pandemic 1918: Eyewitness Accounts from the Greatest Medical Holocaust in Modern History. (New York: St. Martins Press, 2018), 281.

[7] “History of 1918 Flu Pandemic.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention,

March 21, 2018. https://www.cdc.gov/flu/pandemic-resources/1918-commemoration/1918-pandemic-history.htm.

[8]    van Riel, Debby et al. “Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals.” The American journal of pathology vol. 171,4 (2007): 1215-23. doi:10.2353/ajpath.2007.070248

[9] “A Spy Role in Virus Invasion.” Discovery Genetics, January 27, 2020. www.discovergene.com/a-spy-role. 

[10] Ibid.

[11] Ibid.

[12] Akpan, Nsikan, and Kennedy Elliott. “How Coronavirus Compares to Flu, Ebola, and Other Major Outbreaks.” How bad is coronavirus versus the flu and Ebola? National Geographic, February 7, 2020. https://www.nationalgeographic.com/science/2020/02/graphic-coronavirus-compares-flu-ebola-other-major-outbreaks/#close.

[13] Griffiths, James, and Amy Woodyatt. “780 Million People in China under Travel Restrictions over Coronavirus Outbreak.” CNN, February 17, 2020. https://www.msn.com/en-us/health/medical/780-million-people-in-china-under-travel-restrictions-over-coronavirus-outbreak/ar-BB104klw.

 

References:

  1. Arnold, Catharine. Pandemic 1918: Eyewitness Accounts from the Greatest Medical Holocaust in Modern History. New York: St. Martins Press, 2018.

  2. Sipress, Alan. The Fatal Strain: on the Trail of Avian Flu and the Coming Pandemic. Camberwell, Vic.: Penguin, 2011.

  3. “History of 1918 Flu Pandemic.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, March 21, 2018. https://www.cdc.gov/flu/pandemic-resources/1918-commemoration/1918-pandemic-history.htm.

  4. van Riel, Debby et al. “Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals.” The American journal of pathology vol. 171,4 (2007): 1215-23. doi:10.2353/ajpath.2007.070248

  5. “A Spy Role in Virus Invasion.” Discovery Genetics, January 27, 2020. www.discovergene.com/a-spy-role.

  6. Akpan, Nsikan, and Kennedy Elliott. “How Coronavirus Compares to Flu, Ebola, and Other Major Outbreaks.” How bad is coronavirus versus the flu and Ebola? National Geographic, February 7, 2020. https://www.nationalgeographic.com/science/2020/02/graphic-coronavirus-compares-flu-ebola-other-major-outbreaks/#close.

  7. Griffiths, James, and Amy Woodyatt. “780 Million People in China under Travel Restrictions over Coronavirus Outbreak.” CNN, February 17, 2020. https://www.msn.com/en-us/health/medical/780-million-people-in-china-under-travel-restrictions-over-coronavirus-outbreak/ar-BB104klw.