Will the virus that “survives the fittest” eventually become the king?

In 2012, David Quammen, an American science writer who is good at telling stories, published the book Spillover: Animal Infections and the Next Human Pandemic, which looked back at the various infectious diseases faced by humans in the past, and explored and reflected on the relationship between humans, wild animals and nature. He predicted that the next pandemic would still be a virus, and now, his prediction has unfortunately come true. This article is authorized to be excerpted from the sixth chapter of the Chinese version of the book (Spillover, CITIC Press, 2020.6, 2nd edition), "Virus Survival Strategy", which explains the two major characteristics of viruses - infectiousness and toxicity, and explains the significance of different infectious modes and toxicity to viruses from the perspective of virus survival, and uses the example of Australia's introduction of viruses to kill rabbits to see that the "survival of the fittest" virus will eventually win. This article has been slightly edited.

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By David Quammen

Translated by Liu Ying

Proofreading | Zhang Jinshuo, Xu Hengmin

The next viral outbreak, the concept I mentioned at the beginning of this book, is often mentioned by scientists around the world. They think about it over and over again, study it in depth, and are used to being asked questions about it. But so far, the mystery has not been solved. But the idea of ​​the next viral outbreak is always on their minds.

The ultimate infectious disease is now AIDS. Its ultimate power (its reach and its reach) is still unpredictable. About 30 million people have died of AIDS, and about 34 million have been infected, with no end in sight. Polio was also a serious disease, at least in the United States, where it is notorious because it infected a man who later became president of the United States. (Editor's note: Later research showed that Guillain-Barré syndrome was the cause of Franklin Roosevelt's lower limb paralysis.) During the worst years of the polio epidemic, thousands of children suffered from the disease, many of whom were unfortunately paralyzed or even died. The public was stunned by such a rampage, like a deer in the glare of headlights, and was helpless. However, the spread of polio brought about a huge change in the way large-scale medical research was funded and managed.

The biggest infectious disease giant in the 20th century was the influenza pandemic of 1918-1919. Before that, smallpox on the North American continent was also a major threat to the locals. It was part of the expeditionary force that set out from Spain around 1520 and helped Cortes conquer Mexico. Looking back at Europe two centuries ago, the Black Death at that time was probably a form of plague. Regardless of whether the bacteria that caused the plague were bacilli or other more mysterious bacteria (many historians have been arguing about this issue recently), the Black Death was undoubtedly a highly threatening disease that caused human deaths at the time. At least 30% of Europeans died from this infectious disease between 1347 and 1352.

To sum up: if a population is vibrant, has a high population density, and there is a new infectious disease among them, infection is only a matter of time.

You may notice that not all of these pathogens are viruses, but most of them are. Now that antibiotics are widely used and have greatly reduced the mortality rate of bacterial infections, it is safe to assume that the next major outbreak will be a virus.

To understand why some viral outbreaks have such serious consequences, some even cause serious disasters, while others just flash by or disappear quietly without causing any harm, let's consider two aspects of viruses: infectiousness and virulence.

These are two very important parameters, just like speed and mass in physics, which play a decisive role. Together with several other factors, these two factors largely determine the overall scale of the outbreak. Neither is constant, and the relationship between the two is relative. They reflect the connection between the virus and its host and the virus and the outside world, reflecting the external environment, not just the microorganism itself. Infectivity and virulence are the yin and yang of viral ecology.

Different transmission strategies have their own advantages and disadvantages. The simplest description of infectiousness is that viruses need to replicate and spread to survive. You must have heard of this statement before. Viruses can only replicate in host cells, for reasons we have already mentioned. Transmission refers to the transfer of a virus from one host to the next, and infectiousness refers to a series of properties that a virus has to spread.

Can the virus particles accumulate in the host's throat or respiratory tract, causing the host to cough or sneeze, thereby spreading the virus? Once in the external environment, can the virus withstand the test of drying and ultraviolet rays, even for a few minutes? When invading a new individual, can they settle on different types of mucous membranes (nose, throat, eyes), attach to them, and then enter cells to start another round of replication? If all these steps can be completed smoothly, the virus is highly contagious and can be transmitted from one host to another through the air.

Fortunately, not all viruses can be transmitted through the air. If HIV-1 could be transmitted through the air, you and I would probably be dead. If rabies virus could be transmitted through the air, it would be the most terrifying pathogen in the world.

Flu is airborne, which is why new strains can spread around the world in a matter of days. SARS spreads this way, too, or through droplets from sneezes and coughs, floating in hotel corridors and roaming around airplane cabins. That large volume, combined with a mortality rate of nearly 10 percent, is why it struck fear into the hearts of many who knew it in 2003. But other viruses take other routes, each with its own advantages and disadvantages.

Fecal-oral transmission sounds gross, but it's very common. This route works well for some viruses because host organisms (including humans) are often helpless, especially when living in high-density groups, and the water or food they take in is likely to be contaminated by the excrement of other members. This is one of the reasons why children die of dehydration in refugee camps when it rains. The virus enters through the mouth and replicates in the host's abdomen or intestines, causing gastrointestinal disease, which can cause severe diarrhea. Of course, the virus may also spread to other parts of the body.

Diarrhea is an effective transmission strategy for this virus. Viruses that spread this way will have a hard time in the outside world, because they need to stay near sewage wells for a day or two until thirsty people go and drink the water. There is a whole class of viruses that spread this way - enteroviruses, about 70 species including polio. They all attack the human intestine, and most only infect humans, not causing zoonotic diseases. Obviously, they have no need to infect animals, because the crowded human world is enough to sustain them.

The transmission of blood-borne viruses is relatively complex. Generally, this transmission requires a third party - the vector. The virus replicates fully in the host's blood, thus producing a serious viraemia (blood full of virus particles). The vector (a blood-sucking insect or other arthropod) must feast on the host, sip the host's blood and viraemia and take it away. The vector itself must be a hospitable host so that the virus can replicate in their body and produce more viraemia. The viraemia must reach the oral area of ​​the vector and be ready to be released at any time. Then when the vector bites the host, the viraemia is released (just like spitting out anti-hemagglutinating saliva). Yellow fever virus, West Nile virus and dengue virus are all transmitted in this way. This method of transmission has advantages and disadvantages.

The disadvantage is that vector-borne transmission requires adaptation to two very different environments: the bloodstream of vertebrates and the abdominal cavity of arthropods. A virus that grows well in one environment may not survive at all in the other, so the virus must have two sets of genes. The advantage of this route of transmission is that blood-borne viruses have a vector that can carry the virus to new hosts without any complaints or complaints. Air droplets from a sneeze must be carried more or less arbitrarily downwind, but mosquitoes can fly against the wind to their victims. This is what makes vector-borne transmission such an effective route of transmission.

Bloodborne viruses can also be transmitted to new hosts through subcutaneous injections and blood transfusions, but these opportunities for transmission are modern and accidental, a random addition to the traditional routes of transmission that have evolved. Ebola and HIV are two completely different viruses with very different strategies for adapting to their environments, but they both spread well through needles, as does hepatitis C.

As for Ebola, it is also transmitted from person to person through close blood contact, such as when one person is caring for another. In a clinic in Congo, a nurse had cracked hands and small cuts. She spent only a few minutes cleaning the bloody dysentery excrement on the floor of the small clinic, which was enough for her to be infected with Ebola. This is a special mode of transmission, and how the virus spreads depends on itself. The normal mode of transmission of Ebola virus is to spread from individual to individual in some way with the help of a certain transmission medium (still unknown) as its reservoir host.

Ordinary transmission is enough to keep Ebola alive. Exceptional transmission can set off a replication frenzy that makes them extremely notorious, but will soon kill them. In small clinics across Africa, Ebola is transmitted from person to person via bloody rags and reused needles. This is not a long-term strategy for its survival, and it is only an occasional transmission method that has little significance in the broader evolutionary history of Ebola (at least so far). Of course, this situation may change.

Sexual transmission is a good transmission strategy for viruses that have poor resistance to the external environment. This transmission route does not require contact with the external environment, exposure to light and dry air. During mating, the host's genitals and cells on the mucosal surface come into direct and intimate contact, and virus particles can be directly transmitted from one individual to another, and just friction (no pressing) can cause infection.

Sexual transmission is a conservative strategy that reduces the risk of virus transmission and eliminates the need for the virus to find defenses against dryness and sunlight. But this method of transmission also has disadvantages - obviously, the opportunity for such transmission is relatively rare. Even the most lustful humans do not have sex as frequently as they claim. Therefore, viruses that rely on sexual transmission are generally more patient. They have to go through a long incubation period, and slowly replicate (like HIV-1 and hepatitis B virus) in addition to intermittent recurrences (such as herpes viruses), and replicate to a certain extent before they will break out again. This patience of the virus in the host body buys them more time. Using this time, they can meet more sexual partners and continue to spread.

Vertical transmission, from mother to child, is another slow and cautious mode of transmission. Viruses can be transmitted this way when an animal is pregnant, giving birth, or (in the case of mammals) nursing its young. HIV-1, for example, can be passed from mother to fetus through the placenta, through the birth canal to a newborn, or through breastfeeding, but these transmissions are preventable, and medication can reduce the likelihood of mother-to-child transmission. Rubella (often thought of as a form of German measles) is caused by a virus that can be transmitted vertically and through the air, and can kill the fetus or cause very serious damage to the fetus, including heart disturbances, blindness, or deafness. This is why, before the rubella vaccine, it was recommended that young girls be infected with the rubella virus, endure a mild outbreak before reaching childbearing age, and then be permanently immune. However, from a strict evolutionary perspective, relying solely on vertical transmission is not a long-term survival strategy for the rubella virus. A miscarried fetus or a blind child with a heart condition is as likely to be unable to continue the spread of rubella as a Congolese nurse who carried Ebola was the end point of the spread of Ebola.

Regardless of how a virus tends to spread—airborne, fecal-oral, blood-borne, sexually transmitted, vertically transmitted, or simply through the saliva of mammals like rabies—there is one universal truth: transmission alone cannot make a virus spread, and its role is just one side of the ecological yin and yang.

Toxicity, the stronger the better The other side of viral ecology is toxicity, and its meaning is more complicated. In fact, the word toxicity is too flowery and is a relative concept. Some experts don't like to use this word. They prefer "pathogenicity". The two words are almost synonymous, but there is a slight difference. Pathogenicity refers to the ability of a microorganism to cause disease, while toxicity refers to the severity of the disease, especially compared with diseases caused by other similar pathogens. Saying that viruses are toxic may sound like a meaningless repetition, after all, the noun and adjective come from the same root. But if "virus" is restored to its original name "toxic mucus", then hearing "pathogenicity" will make you ask: "How toxic is it?"

What does toxicity tell you? This is the most complicated part. When it comes to toxicity, most of us have heard the old story: the first rule of successful parasitism is not to kill the host. One medical historian traced this idea back to Louis Pasteur, who pointed out that the most effective parasites are those that "can coexist harmoniously with the host," so asymptomatic infection should be "the ideal state of parasitism." Zinsser made the same point in "Mice, Lice, and History." He observed a parasite and a host over a long period of time, and found that the two constantly adapted in evolution, and eventually "the invader and the invaded reached a state of mutual tolerance." Macfarlane Burnett agreed:

In short, when two organisms develop into a host-parasite relationship, the parasite can survive only because the host provides it with the best service. Instead of being destroyed by the host, the parasite develops a balanced and harmonious relationship with the host. The substances in the host organism are sufficient to provide energy for the growth and replication of the parasite, and the energy consumed does not cause the death of the host.

At first glance, this seems to make sense, but some people - at least those who have not studied the evolution of parasites - think this view is arbitrary. However, even well-known experts such as Zinsser and Burnett have not directly answered why they believe this view. They must know that this "law" is just a generalization of individual cases, which has some meaning. But some famous viruses do kill their hosts, with a mortality rate of 99%, and they can maintain this record for a period of time. Rabies virus and HIV-1 are the most appropriate examples. However, the key issue is not whether the virus kills its host, but when it kills.

“A pathogen that kills its host quickly also puts itself in danger of survival,” wrote historian William H. McNeill in his landmark 1976 book Plagues and Peoples, “because it must find new hosts very quickly and frequently to ensure its survival and continuation.” McNeill was right, and the key word in that sentence is “rapidly.” Time is life, and pathogens that kill their hosts slowly, although cruelly, avoid survival.

The infectiousness and toxicity of viruses constantly influence and interact with each other, maintaining a dynamic balance. Where is the balance point of this dynamic balance? It depends on the situation. Some viruses can be transmitted for a long time even if they kill all their hosts, because they can find the next host before the previous host dies. This is the case with rabies virus, whose hosts are usually dogs, foxes, skunks or other carnivorous mammals, which generally have sharp teeth and are fond of eating meat. Rabies virus infects the host's brain, causing the host's behavior to suddenly burst into aggressiveness, thereby inducing the mad host to bite wildly. During this period, the virus also infects the host's salivary glands, so it can successfully infect the victim who is bitten. Even if the original host dies in the end, or is killed by the old rifle of lawyer Atticus Finch (Editor's Note: A character in the novel "To Kill a Mockingbird" by American writer Harper Lee), the virus's transmission is still unaffected.

Rabies sometimes occurs in cattle and horses, but it is rarely heard of, probably because herbivores rarely bite in anger and spread the virus. A rabid bull might howl pitifully or run headfirst into a wall, but it is unlikely to be seen raging and raging on passers-by on a country road. In East Africa, there are occasional reports of rabies outbreaks in camels, which worries camel herders, because the most annoying thing about dromedaries is that they bite people. A dispatch from the northeastern border of Uganda reported that a rabid camel went crazy, "jumping up and down, biting other animals and eventually dying." Another case came from Sudan, where a rabid camel became extremely agitated, sometimes destroying inanimate objects and sometimes biting its own legs. Biting its own legs is not a big deal, but it reflects the persistence of the virus. Even humans infected with rabies may spread the disease by biting others when they struggle violently in the late stages of the disease. According to the World Health Organization, there have been no confirmed cases of this, but sometimes some precautions are taken. A few years ago, a Cambodian farmer was bitten by a rabid dog and contracted the disease. In the later stages of the disease, he had hallucinations and severe convulsions, and finally the situation became worse and worse. "He barked like a dog." His wife later recalled, "We tied him with a chain and locked him up."

HIV-1, like rabies, kills almost all of its hosts. If you think about which virus was the most deadly, in the dark decades before combination antiretroviral therapy came into effect, it was undoubtedly HIV-1, and it probably still is (time will tell). Death rates have fallen among several categories of HIV-positive people (mainly those who can afford an expensive "cocktail," a combination of drugs), but no one would dare to say that the virus itself is becoming milder.

HIV is essentially a slow-moving organism, so it is classified as a slow virus along with other slow-moving viruses such as sheep myelin sheath virus, feline immunodeficiency virus, and equine infectious anemia virus. HIV-1 can enter the human blood circulation and survive in the human body for a decade or more, during which time it gradually and slowly replicates, evading the body's defense system, causing large fluctuations in the number of viruses, and destroying cells that regulate immune function bit by bit. Finally, mature HIV delivers a fatal blow. In this process, especially in the early stages of infection (when the virus blood level is high but before it drops back), the virus has ample time and opportunity to spread from person to person. Later, when we studied how HIV spread in the first place, the virus gained more time and opportunity to infect. At the same time, it can be fully demonstrated that evolution may induce HIV to undergo a variety of changes, a variety of adaptations, and a variety of new tendencies, but there is no reason to imagine that any type of variant will be less lethal.

The most famous example of reduced viral virulence is the myxoma virus in Australian rabbits. This example has become a paradigm case. Myxomatosis is not a zoonosis, but it has played a small but important role in helping scientists understand how viral virulence is regulated in evolution.

Which type of virus survives in the end? The story takes place in the mid-19th century. A white landowner, Thomas Austin, had a sudden idea to introduce wild rabbits from Europe to Australia. He was not the first person to introduce rabbits to Australia, but he was the first to introduce wild rabbits. He raised them on his estate in Victoria, the southernmost state of mainland Australia. These rabbits were not bound by their homes and could survive in the wild, so they naturally reproduced very quickly (after all, they were rabbits). If he just wanted to enjoy the pleasure of hunting rabbits or use rabbits as prey for hunting dogs, then the actual situation was far from what he imagined. In just six years, 20,000 rabbits were killed on his estate, and countless rabbits escaped from all directions of the estate.

By 1880, the rabbits had crossed the Murray River into New South Wales, and from there they continued to spread north and west. The vanguard of this rabbit army advanced at a formidable pace of about 70 miles per year, including the occasional stops to rest and breed. As the decades passed, there was no doubt that the situation was getting worse. By 1950, there were an estimated 600 million rabbits in Australia, competing with local wildlife and livestock for food and water. The Australians had finally gotten over it and decided to take immediate action to control the rabbits.

In the same year, the Australian government agreed to import a rabbit pox virus from Brazil, which is a myxoma. This virus infects Brazilian rabbits, but does not cause much harm. In Brazil, it only causes small skin ulcers in familiar hosts, which do not expand and slowly heal. However, Brazilian rabbits belong to the South American forest rabbit, and experiments have shown that the consequences of European rabbits being infected with this American virus are extremely serious.

Yes, myxoma did kill about 99.6% of the infected rabbits like a plague. The rabbits also developed ulcers, but not small patches, but large ulcerative lesions, not only on the skin, but on all organs of the body, and the condition was so serious that the rabbits died within two weeks of infection. The virus is mainly transmitted by mosquitoes, and Australian mosquitoes are not only large in number, bloodthirsty, and hungry for the blood of new species. The virus seems to be transmitted physically rather than biologically, that is, the virus particles stick to the mosquito's mouth, rather than replicating in the mosquito's stomach or salivary glands to produce toxic substances. This physical method of transmission is the clumsier form of vector transmission, simple, and in some cases effective.

After several experimental releases of the virus, myxoma took over the rabbits in the Murray Valley, causing a "spectacular epizootic." This may be because the speed and scale of the disease's spread "are unprecedented in the history of infectious diseases." This is thanks to mosquitoes and the breezes that they ride on, otherwise the virus would not have spread so quickly. Thousands of rabbit carcasses piled up like small mountains in Victoria, New South Wales, and Queensland. Except for those who sympathize with rabbits and make a living from cheap rabbit fur, this result is simply a happy ending. In ten years, two things happened: First, the virus became less toxic, and the surviving rabbits became more resistant to the virus. Second, the mortality rate dropped, and the rabbit population began to rebound. From a simple perspective, in the short term, this is what happened, and a simple conclusion can be drawn: evolution can reduce the toxicity of the virus, and the virus and the host tend to a state of "more mutual tolerance."

But that's not quite right. The truth was teased out through careful experiments by an Australian microbiologist named Frank Fenner and his colleagues. In fact, the virulence of the virus drops rapidly from an initial limit of more than 99%, then levels off at a relatively low level, but still quite high.

Can you believe that a “mere” 90% mortality rate makes the virus and host tolerant of each other? I don’t believe it either. The maximum toxicity of this virus is as high as the mortality rate of Ebola virus in rural Congo. But Fennell found that it was. He and his colleagues collected many virus samples from the wild, tested them on clean and healthy rabbits in captivity, and then compared the infection status of each sample one by one to study the changes in the toxicity of the virus. They found that the variants of this virus have a wide variety. For analysis, they divided these variants into five grades of Australian myxoma from high to low mortality. Grade 1 is the original variety, with a mortality rate of nearly 100%; Grade 2 has a mortality rate of more than 95%; Grade 3 is in the middle of the five grades, with a mortality rate of 70% to 95%; Grade 4 is slightly milder; Grade 5 is an attenuated version of the virus (causing very mild symptoms), very few rabbits will die, and it is very suitable for use as a vaccine.

What proportion of the infected rabbits are made up of each of the five classes? By collecting samples from the wild, testing for the presence of each class, and tracking changes in predominance over time, Fennell and his colleagues hope to answer some basic questions, including: Is the virus really becoming less virulent? Is the mutual evolution of rabbits and microbes moving toward what Zinsser calls "better mutual tolerance," like a harmless fifth class? Will myxoma learn to kill its host?

The answer was no. A decade later, Fennell and his colleagues found that grade III myxomas dominated, still killing more than 70 percent of rabbits, accounting for more than half of all samples collected. The most lethal type (grade I) had almost disappeared, and the least harmful type (grade V) was still rare. The situation seemed to have stabilized.

But has it really stabilized? Ten years is just a blink of an eye in the long journey of evolution, even for fast-reproducing viruses and rabbits. Fennell continued to observe.

Another 20 years later, he reported a significant change: by 1980, Class III myxomas had made up half of the samples collected, but now made up two-thirds. High mortality rates, but not always fatal, Class III myxomas thrive in the wild, an example of successful evolution. The very mild variety, Class V, has now disappeared, not because it was uncompetitive, but because, for some reason, it seemed to fail Darwin's test: the unfit are eliminated.

How to explain this unexpected result? Fennell astutely speculated that the dynamic relationship between viral toxicity and transmissibility might explain it all. He tested all the viruses one by one on captured rabbits and mosquitoes, and found that the transmission efficiency was related to the number of available viruses on the rabbit's skin. The more lesions, or the longer the lesions last, the more available viruses there are. The more viruses on the mosquito's mouth, the greater the chance of transmission. But "available viruses" are assumed to be from live rabbits, still bleeding, that is, the vector is still interested. Dead and stiff rabbits will not attract the attention of mosquitoes. Between the two extreme infection results, that is, between cured rabbits and dead rabbits, Fennell found a balance point.

“Laboratory studies have shown that all strains capable of producing lesions provide sufficient virus for transmission,” he wrote. But the highly pathogenic strains (grades 1 and 2) killed rabbits quickly, “so quickly that the lesions remained infectious for only a few days.” The milder strains (grades 4 and 5) produced lesions that healed quickly. The revenge for the rapid healing, he added, was that “rabbits infected with grade 3 remained highly infectious for the time before they died, and those that survived remained infectious for longer.” At that point, grade 3 still killed about 67 percent of the rabbits exposed to it. After three decades of research, Fennell found that the extremely lethal level of myxoma virus maximized its transmissibility. The virus killed most infected rabbits while also ensuring its own survival, sustaining a continuous infection.

Is this the first successful example of a parasite? The success of myxoma in Australia suggests something different than the conventional wisdom I mentioned earlier. It's not about not killing your host, but about not burning your bridges.

As for who created such rules, it is just evolution. Later, scientists established the epidemic dynamics model (SIR) and proposed the basic reproduction rate of infected people, which can reflect the best strategy for virus evolution. The virus is directly related to its transmission rate in the host population, and has an opposite and complicated relationship with its pathogenicity, cure rate and natural mortality caused by other reasons. But it still depends on the specific situation of transmissibility and toxicity. This depends on ecology and evolution.

RNA viruses have a high mutation rate and a large number of mutations, which will cause the virus to have more adaptive changes. This virus strives to compete with the immune system of each host, strives to gain the upper hand, and evacuates quickly with everything it needs before the host's defense system repel them, and then continues to move forward.

But DNA viruses exhibit the opposite extreme characteristics. Their mutation rate is very low and their overall number is not large. Seeking self-preservation and immortality has become their survival strategy, and they tend to take the route of a protracted war.

If you were this stuck virus, with no long-term security, no time to waste, no bets to lose, and only the ability to adapt to new environments, what would you do? Until now, the research we have done has been around the question that I am most interested in - "They often select between species." Virus expert Edward C. Holmes said.