by Nathan Wolfe
Image from the sylvatic dengue study. (Institute of Medical Research Malaysia / A. Rudnick, T. Lim)
The capacity for sylvatic dengue to thrive in multiple species presumably helps the virus persist in regions where the population density of any single primate species would not be sufficient to protect the virus from extinction. And the mechanism dengue uses to move from one animal to another—mosquitoes—helps make this movement seamless.
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For dengue, the notion of a single reservoir does not, strictly speaking, make sense, but when Nipah was discovered in 1999, that was still unclear. Scientists then asked themselves: what local animal or animals, wild or domestic, were Nipah’s reservoir? Knowing what animal or animals a virus lives in prior to infecting humans helps us respond to it. Depending on the reservoir, we may have the potential to simply change farming practices or modify human behavior to avoid the critical contact that leads to viral exchanges, effectively cutting off the virus’s ability to enter humans.
Knowing that a microbe has the capacity to maintain itself in an animal reservoir also changes the way that we think about public health strategies. Microbes can jump in both directions, so while novel human microbes like Nipah originate in animals, established microbes also have the potential to cross back into animals. Animal reservoirs for established human bugs can potentially derail control efforts. In effect, if we eliminate a bug in humans in a particular region, but it lives on in animals, the microbe may have the potential to reemerge with deadly consequences. In order to truly eradicate a human pathogen, we must know if it can also live outside of humans.
When Nipah emerged in 1999, the scientists studying it moved quickly to home in on its reservoir. Over the years that followed, an intricate relationship among wild animals, domesticated animals, and plants revealed itself, a story that emphasizes the complex ways that domestication can provide new avenues for bugs to pass into people.
The Malaysian piggeries that Nipah entered are not small-scale affairs. They house thousands of pigs at very high densities, creating a ripe environment for viral spread. The farmers who raise the pigs work hard to maximize their income both from the pigs themselves, but also from the surrounding land. One of the practices in this area of southern Malaysia is to grow mango trees in and around piggeries, providing a second source of income to increase the viability of the farming enterprise.
In addition to producing delicious fruit for the farmers to sell, the mango trees attract the flying fox, a large and appropriately named bat with the scientific name Pteropus. This bat was the unexpected Nipah reservoir, the virus’s link to the wild. Remarkably, it now appears that the Pteropus bats, while consuming their mango suppers, urinate and drop partially eaten mango into the pig pens. The omnivorous pigs consume the Nipah-infected bat saliva and urine as they eat the mango. The virus then spreads quickly in the dense pig populations, which, because the animals are sometimes shipped from place to place, infect new piggeries and occasionally infect their human handlers.5
Wahlberg’s Epauletted Fruit Bat (Epomophorus wahlbergi) eating mango. (Dr. Merlin D. Tuttle / Bat Conservation International / Photo Researchers, Inc.)
Emerging thousands of years after the advent of domestication, Nipah illustrates the impact that domestication had on our relationship with microbes. The larger and more sedentary populations of humans that emerged following the domestication revolution were susceptible to outbreaks in ways that our predomestic ancestors never were. In the small mobile communities that dominated human life prior to agriculture, novel microbes that entered these communities from animals would often sweep through, killing certain individuals and leaving the rest of the small populations immune. At that point the viruses would effectively die out; a virus without a susceptible host is unable to survive.
As villages and towns formed around agricultural centers, they did not do so in isolation. Communities were connected, at first with footpaths, then roads. While we might think that these towns were separate functional entities, from the perspective of a microbe, they represented a single larger community. As this interconnected community of towns grew, it provided the first opportunity in human history for an acute virus to persist permanently in the human species.
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Chronic viruses that live permanently within their hosts, like hepatitis B, do not necessarily require large populations because they can continue to pass on their progeny for many years. These viruses have the potential to persist in very small communities, taking a long-term strategy—he who fights and hides away lives to fight another day. On the other hand, acute viruses, such as measles, do not remain in a single individual for long and require a constant supply of susceptible hosts. As they burn through populations, they kill some and make the rest immune, often leaving no one to perpetuate the infection.
Therefore, within the small, mobile hunter-gatherer lifestyle that our ancestors led prior to domestication, acute viruses could not survive for long unless they were microbes that we shared with other species. In the same way, chimpanzee populations, including those that were studied by the pioneering primatologist Jane Goodall, have sometimes been hit with polio. The virus that causes polio normally requires large populations of contemporary humans to sustain itself. Nevertheless, in 1966 Dr. Goodall and her colleagues saw that the wild chimpanzees they studied had come down with something that looked very much like human polio, including symptoms of flaccid paralysis. The outbreak was devastating for the chimpanzee community in Tanzania, killing a number of animals.
The virus that caused chimpanzee polio was in fact the same virus that caused polio in humans. It had jumped over from nearby humans who were experiencing an outbreak at the same time. Dr. Goodall and her colleagues administered vaccine to the chimpanzees, which no doubt limited the harm to the community. Chimpanzees, like our early human ancestors prior to domestication, would not have had the population sizes to maintain such a virus—current estimates suggest that communities of over 250,000 people are necessary to sustain it. In small communities, the virus would simply have swept through, harming some and creating immunity in the others, before dying out.
But when our ancestors, with their farms and domestic animals, began to have interconnected towns, viruses like polio gained the ability both to infect us and to be maintained within our species. As more and more towns appeared and the connections between them improved, the number of people in contact with each other increased. From the perspective of a microbe, the physical separation of these towns didn’t matter if there were enough people moving between the towns. Hundreds, and later thousands, of interconnected towns effectively became a single megatown for microbes. Eventually, the number of interconnected people would become so large that viruses could maintain themselves permanently. As long as new people entered into the populations through birth or migration, and did so with enough frequency, there would always be a new person for the microbe to try.
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In effect, domestication provided a triple hit to our ancestors when it came to microbes. It provided sufficiently close contact with a small set of domesticated animals, allowing their microbes to cross over into us. At the same time, domestic animals provided a regular and reliable bridge to wild animals, giving their microbes increased opportunities to cross into us. Finally, and perhaps most crucially, it permitted us to have large and sedentary communities that could sustain microbes that previously would have been a flash in the pan. Together, this viral hat trick put us in a new microbial world—one that would lead, as we’ll see in the next chapter, to the first pandemic.
PART II
THE TEMPEST
5
THE FIRST PANDEMIC
In early July 2002 in Franklin County, Tennessee, a thirteen-year-old boy named Jeremy Watkins picked up a sickly bat on his way home from a day of fishing. None of the other family members handled it, and his stepfather wisely made him release the animal soon after Jeremy revealed his find.
Ev
ents like this happen all over the world with thousands of wild animals every day, largely without ill consequences. But Jeremy’s encounter with this particular bat would be quite different.
In the CDC report that would document Jeremy’s case, the next events were described with clinical efficiency. On August 21 Jeremy complained of headache and neck pain. Then a day or so later his right arm became numb and he developed a slight fever. Perhaps of greater concern, he also developed diplopia, or double vision, and a constant, queasy confusion. Three days later he was taken to the local hospital’s emergency room but was discharged with the incorrect diagnosis of “muscle strain.” The next day he was back in the emergency room, this time with a fever of 102°F. He had the same symptoms, but now his speech was slurred, he had a stiff neck, and difficulty swallowing.
At this point, Jeremy was transferred to a local children’s hospital. By August 26 he could no longer breathe or think normally. He was also producing copious amounts of saliva. Highly agitated to the point of being combative, Jeremy was sedated and put on life support. His mental status deteriorated rapidly and by the next morning he was completely unresponsive. On August 31 Jeremy was pronounced brain-dead and, following the withdrawal of life support, he died of bat-borne rabies.
Jeremy’s family did not know that bats could carry rabies, much less transmit it to humans. They did not remember him complaining of a bite, although that’s exactly what must have happened while he carried the bat home from his fishing excursion. They probably did not know that the incubation period for rabies is generally three to seven weeks, well within the range of the time between his exposure to the bat and the first symptoms he experienced. Detailed studies of the virus that killed Jeremy revealed evidence of a variety of rabies found in silver-haired and eastern pipistrelle bats common in Tennessee.
Rabies is a terrible way to die. It’s a disease that devastates the families of its victims, with patients becoming virtual zombies in the days before death. It is among the small number of viruses that kill virtually all of the individuals they infect. But as tragic as it is that the doctors at the local Franklin County emergency room sent Jeremy home with a diagnosis of muscle strain, the reality is that it was already too late to help the boy at that point. Without rapid postexposure prophylaxis after infection, the boy was destined to die.
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If we take a different view, the virus that causes rabies is not only a deadly menace but also a truly amazing feat of nature. This virus, shaped like a bullet, is a meager 180 nanometers long and 75 nanometers across. If you stacked rabies viruses one on top of the next, you would need more than a thousand of them to reach the thickness of a single human hair. Rabies has an almost trivial genome, with only twelve thousand bits of genetic information for a meager five proteins. It’s simple, tiny, and incredibly powerful.
While diminutive, the virus accomplishes remarkably sophisticated tasks. In addition to the standard viral work of invading cells, releasing genes, making new viruses, and spreading, it has some unique tricks. From the point of entry, the virus travels preferentially along neural pathways, making its way into the central nervous system. It accumulates selectively in the saliva. The virus particles that infect the central nervous system modify the host’s behavior, increasing aggression, interfering with swallowing, and creating a profound fear of water. When put together, a rabies infection leads to an aggressive host literally foaming at the mouth with virus. A host that lacks the capacity to drink or swallow further increases the probability of delivering a successful bite—a bite that gives this particular virus the ability to advance from one individual to the next.
Hospitalized human rabies victim in restraints. (Courtesy of the Centers for Disease Control)
As frightening and deadly as rabies is, as a global community we need not fear it. That a virus is exceedingly and dramatically deadly does not mean it will become a pandemic. Rabies kills more than fifty-five thousand people a year worldwide. It is a cause for serious public health measures, but it does not present a global pandemic threat. In all of the years that the CDC and other public health organizations have followed rabies, it has never once gone from person to person. Every one of those deaths, like the death of Jeremy Watkins, resulted from an independent animal infection. From a pandemic perspective, it doesn’t have the right stuff.
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So, what is a pandemic? Defining them creates some trouble. The word itself comes from the Greek pan, meaning “all,” and demos, meaning “people.” Yet, in reality, it is almost impossible to imagine an infectious agent that infects the entire human population, a high bar to set for a virus. In humans or any hosts, different individuals will have different genetic susceptibility, so at least a few individuals will likely be incapable of sustaining an infection because of some kind of genetic immunity. Also, the simple logistics of spreading to every single individual in any population makes such a feat nearly impossible.
Among the most common viruses infecting humans that we are aware of is the human papilloma virus,1 and it doesn’t afflict 100 percent of people. HPV currently infects 30 percent of women between the ages of fourteen and sixty in the United States, a whopping high rate for a virus. Rates are likely even higher in some parts of the world. Amazingly, the majority of sexually active humans on our planet, whether male or female, will get HPV at some point in their lives. The virus is made up of over two hundred different strains, all of which infect either skin or genital mucosa. Once the virus enters an individual, it generally stays active for years or even decades. Fortunately, the vast majority of HPV strains cause no problems for us. The few strains that do cause disease generally do so by causing cancer, the most important example being cervical cancer.2 Luckily, most HPV simply spreads from individual to individual with little harm.
We’re still aware of only a small percentage of all viruses that call humans their home. There may be viruses out there that infect even more people than HPV does; the work to identify all of the viruses that infect us has only just begun. Research over the last ten years has identified multiple previously unknown viruses circulating in humans that infect many individuals yet do not appear to cause any illness. The TT virus was named after the first individual to be infected, a Japanese man with the initials T.T. Very little research has been done yet on TTV, but it may be quite common in some locations. A report by one of my collaborators, Peter Simmonds, an excellent Scottish virologist, found prevalence rates ranging from 1.9 percent among Scottish blood donors to 83 percent among residents of The Gambia in Africa, a startlingly high range. Fortunately, TTV does not appear to be harmful.
GB virus is another recently identified and still largely unstudied virus present in many people. The virus got its name from a surgeon, G. Barker; at the time, his hepatitis was mistakenly attributed to the virus.3 I know from my own work how common both TTV and GBV are. Using very sensitive approaches to viral discovery, we frequently see these two—largely to our dismay, since they interfere with our ability to catch the dangerous culprits we’re really looking for.
However common TTV and GBV are, they do not infect 100 percent of humans. So the literal Greek-derived definition of pandemic is probably an impossibility. The World Health Organization (WHO) has devised a six-stage classification of pandemics beginning with a class-one virus that infects just a few people and going on to a class-six pandemic, which occurs when infections have spread worldwide.
The WHO faced widespread criticism for labeling H1N1 a pandemic in 2009, but that’s exactly what it was. H1N1 went from infecting only a few individuals in early 2009 to infecting people in every region of the world by the end of the same year. If that’s not a pandemic, then I don’t know what is. Whether or not we label a microbe that’s spreading as a pandemic is unrelated to its deadliness. It’s just a marker of its ability to spread. And as we discussed in chapter 1, the fact that H1N1 doesn’t kill 50 percent of the people it infects (or even 1 percent for that matter) doesn’t mean it wo
n’t kill millions of people or represent a massive threat.
In fact, from my perspective, it’s possible that we could have a pandemic and not even notice it. If, for example, a symptomless virus like TTV or GBV were to enter into humans today and spread around the world, we probably wouldn’t be able to tell. Most conventional systems to detect diseases only catch things that cause clear symptoms. A virus that didn’t cause any immediate harm would likely be missed.
Of course, “immediate” isn’t the same thing as “never.” If a virus like HIV were to enter into humans today and spread globally, it wouldn’t be detected for years, since major disease would occur sometime after initial infection. HIV causes only a relatively minor set of syndromes immediately, even though it starts to spread right away. AIDS, the major disease of HIV, doesn’t emerge until years later. Since conventional methods for detecting new pandemics rely primarily on seeing symptoms, a virus that spreads silently would likely miss our radar, spreading to devastating levels before an alarm could be triggered.
Missing the next HIV would obviously be a catastrophic public health failure. Yet new viruses, even if likely to be completely harmless, like TTV and GBV, need to be monitored if they are moving quickly through the human population. As we saw in chapter 1, viruses can change. They can mutate. They can recombine with other viruses, mixing genetic material to create something new and deadly. If there’s a new virus in humans and it’s spreading globally, we need to know about it. The dividing line from spreading and benign to spreading and deadly is a potentially narrow one.