Global Monkeypox outbreak provides an unprecedented opportunity to adapt to humans. Will the situation get worse?
Since May, monkeypox virus has shown in color transmission electron microscope photos that have caused nearly 60,000 people around the world to get sick.
Several years ago, researchers searched the remains of 1867 people who lived between 30,000 and 150 years ago to find genetic traces of the virus that causes smallpox, the Valora virus. Among the teeth and bones of the four Nordic from the Viking era, they found enough DNA to reconstruct the entire variant genome. These sequenced viruses are not the direct ancestors of the terrible variant viruses that were eradicated in the second half of the 20th century. But they may know how smallpox has become so deadly.
In a 2020 paper published in the journal Science, researchers reported that Viking virus has lost several genes over a period of 350 years. Researchers have seen this pattern before. Modern smallpox viruses have also recently lost several genes, although due to different mutations. The two observations “show that the loss of genes was not accidental”, said poxvirologist Antonio Alcami of the Severo Ochoa Centre for Molecular Biology in Madrid. "It was chosen." Alcámi believes that these losses could make Valora more virulent, resulting in its 30% mortality rate. In the past, smallpox could have been a “widespread mild disease,” he wrote in an opinion piece. Now, some scientists are thinking: Will such a thing happen again?
Since May, the monkeypox virus (Variola) has been spreading around the world, giving the virus unprecedented changes and opportunities to adapt to the human population. Will it evolve into more contagious or lead to more severe illness? No one knows, but the recent history of SARS-CoV-2 provides a sober lesson.
After the emergence in Wuhan at the end of 2019, the virus first produced a series of variants that may have spread much faster than their ancestors, and then evolved further to escape human immunity. Its tricks surprised even some scientists who have long studied virus evolution. "If a new virus is entering a space without immunity, then rapid adaptation will happen," said Aris Katzourakis, an evolutionary virologist at at Oxford University. "Monkey Pox can bring equally unpleasant surprises to humans.
In July, researchers in Berlin published a preprint that analyzed the viral genome sequences in lesions in 47 monkeypox patients. In addition to many minor changes, they discovered a virus in which one gene was copied and the other four simply disappeared. The final paragraph of the paper reads like a warning: "The consequences of the context of the poxvirus gene change or other alteration of its product are no longer needed in a new host," the authors said. The phenotype of monkeypox virus we know in the past 64 years may not be like that of the human "monkeypox" that has been around for a while.
Many researchers say we should not worry too much now. Virologist Geoffrey Smith of the University of Cambridge suspects that monkeypox virus will soon become a more virulent virus. As we all know, the large amount of genomes of poxvirus have evolved slowly, and they are not very easy to adapt to the immune system, just like SARS-CoV-2 does. SARS-CoV-2 is a highly contagious respiratory pathogen that infected hundreds of millions of people in the first year of birth;
Monkeypox is mainly transmitted in men who have sex with men, and has only reported about 60,000 cases so far, so its chances of evolution are much smaller. However, this may change.
Bernard Moss, a senior poxvirus researcher at the National Institute of Allergy and Infectious Diseases, said that a "bad situation" is that the virus evolves faster in humans. This will infect more people, which in turn will accelerate its evolution and may make it better at infecting humans.
At present, monkeypox virus is not good at infecting humans.This is a versatile person who seems to thrive in a range of animal species in sub-Saharan Africa (most of which are rodents). The virus spreads to people from time to time, and these people sometimes infect several others. Although the frequency of outbreaks has increased in recent years (see "Outlook"), they are usually smaller in scale. After each appearance, the virus obviously disappeared from humans again.
This time it is different because monkeypox continues to spread from person to person worldwide. "We have never seen this virus have such a chance to adapt to humans before," said Terry Jones, a computational biologist at the Charité University Hospital in Berlin, who is one of the authors of "July Preprint".
The viral genealogy mutation found in monkeypox samples allowed researchers to track the root causes of the current outbreak in Nigeria. The virus has been exported to other countries many times and eventually spread around the world. Because APOBEC 3, a human protein, may introduce many mutations, they can also show how long the virus spreads in the human body.
In many Western countries, reported cases are declining -- most likely due to behavioral changes and vaccination -- and public health officials in Europe are already discussing eliminating the virus in the region. But in other parts of the world, infections are still rising. In many places, people who are not vaccinated, or at risk, either lack information on how to avoid infection or are afraid to seek infection, because homosexual sexual behavior is criminalized.
"I don't think monkeypox will cause a lot of infection, but it will stay there and be hard to eradicate," said Alcámi. "Decision makers must realize that this is not going away anytime soon," added Christian Drosten, a virologist at Charité, who is one of the co-authors of The July preprint.
As the virus continues to spread, science can only hint at how the virus evolves. One reason is that after the global smallpox eradication campaign won the victory in 1980, people's interest in research on poxvirus has weakened. "I always start my conversation in an almost apologetic way because I'm studying poxvirus," Alcami said. Evolutionary virologists have turned to focus on influenza viruses, HIV and other small viruses made of RNA. In contrast, the pox virus is made of DNA, and is much larger and more complex. The monkeypox genome has about 200,000 nucleotides and 200 genes, which is more than 20 times that of HIV. It is unclear which of these genes work, let alone how they interact, and what impact any of their changes may have on humans, Moss said. The host of monkeypox virus is not known, but many rodents in Africa seem to be able to carry it, including African kangaroos (Cricetomys eminitop) and fire-footed squirrels.
For years, Moss has been trying to find out the key difference between the two variants of monkeypox virus: CLADE 2, which was only recently discovered in West Africa , is now causing a global outbreak; Clade 1, believed to be the more lethal virus, has been outbreaking in Democratic Republic of the Congo for decades. He found that the Clade 1 virus can kill mice 1,000 times the level required by Clade 2. To find out why, Moss and his colleagues converted dozens of Clade 2 genes to Clade 1 viruses at a time, hoping to see it become less deadly, but so far there is no luck. Now, they are planning to make the opposite attempt, conferring the clade 2 virus genes from its deadly relatives. However, one thing is clear: poxvirus mutations slowly compared to RNA viruses. "Their genomes are fairly stable and won't change anytime soon," Smith said. Although poxviruses have ways to deceive the immune system, they won't change surface proteins like SARS-CoV-2 to escape the epidemic. Smallpox infection, if you survive, can provide lifelong immunity, and the vaccine remains effective until the end of the eradication exercise.
This also provides some hope that monkeypox will not become a bigger threat.Researchers around the world are digging out the monkeypox genome from recent patients to understand how the virus has evolved so far. Obtaining high-quality sequences is harder and more expensive than SARS-CoV-2, not only because the monkeypox genome is so large, but also because the key regions at its ends may be full of repetitions or deletions, which may confuse researchers when assembling the sequence. "Treatment of these genomes is much more complicated than RNA viruses," said Richard Neher, a computational biologist at the University of Basel, . "People share raw data will be more important than SARS-CoV-2."
Still, some results have been achieved in this work. When the researchers compared the recent genome of the current monkeypox outbreak with older sequences, they quickly discovered two interesting things, such as the genome isolated from a traveler from Nigeria, England in 2019. Just a few years later, the genome showed more point mutations than expected, many of which followed the same pattern, with the nucleotide combination guanine-adenine conversion to adenine or thymine-cytosine conversion to thymine-thymine.
Viral DNA found in Viking bones suggests that the loss of some genes may make the smallpox virus more virulent. B.M.hlemann et AL., Science (2020)
These mutations may be traces of the ongoing battle between the virus and the human immune system. A human protein called APOBEC 3, as a cellular defense mechanism, introduces errors when replicating in the viral genome, and the changes found in the monkeypox genome are its mark. "It's obvious that stopping virus replication is not enough," said Andrew Rambaut, a molecular evolutionary biologist at the University of Edinburgh, . However, in the long run, mutations may make the virus less suitable as it accumulates, or one of them may benefit the virus. Still, “My intuition is that from an evolutionary perspective, it may not be very important,” Rambaut said.
What these mutations can do is give researchers a clock to determine how long ago monkeypox began to spread in humans. Edinburgh evolutionary biologist Aine O'Toole said that by comparing genomes at different time points, the virus currently adds about 6 changes associated with APOBEC 3 per year.
The viral genome family of this epidemic shows that the virus that was prevalent in Nigeria at the end of 2017 had carried nine apobecc type 3 mutations, which means that the virus entered humans sometime in early 2016, about a year and a half before the outbreak in Nigeria (see the picture above). The analysis also shows that the virus has been spreading in humans since then. But poxvirus can evolve in other more intense ways, rather than changes in single nucleotide . Nels Elde, a virologist at the University of Utah, said they "did a lot of evolutionary off-roading" and turned to monkeypox after studying vaccinia for many years. vaccinia is a weakened poxvirus as a smallpox vaccine.
Elde explained that the poxvirus genome is usually composed of a central region with about 100 genes, mostly associated with new copies of the virus, and the terminal region has about 100 genes that interact with the host, such as genes that fight immune defenses. These terminal genes appear to be key sites for evolution. Common poxviruses infected with many different hosts, including monkeypox and cowpox, tend to have more genes in the terminal area, while much less smallpox is specifically infected with humans. Most researchers believe smallpox evolved from a rodent poxvirus that jumped to humans. Hendrik Poinar, a molecular evolutionary geneticist at McMaster University , said over time, gene loss, such as genes found in Viking viruses, could make it more deadly.
1938 A teenage boy received a smallpox vaccine in GasPort, New York (first image), and people lined up to get vaccinated in New York City (second image). The work of eradicating smallpox completed in 1980 has weakened people's interest in research on poxvirus."Smallopsis goes from what we think is actually a very nontoxic form, to the repetitive gene inactivation, and it doesn't get very disgusting until we eradicate it," Poinar said. According to a 2020 scientific paper and his own research on the genome of variants in 17th-century children's mummies, Poinar believes this happened between the 4th and 15th centuries. However, how the loss of genes will make the variant more virulent is unclear.
Eugene Koonin, a researcher at the National Center for BioTechnology Information, said simply having a smaller genome may make viruses better at replicating in human cells. "It's a big deal to make replication 10% faster," Koning said. "Once this happens, this variant will quickly outperform the competitors." The terminal genes can also evolve through another mechanism. They are often replicated during virus replication, which can help the virus in two ways. These additional copies allow it to quickly produce more of the required protein, and they increase the chance that at least one copy of the gene will undergo beneficial mutations. "Improvement" can make other copies redundant, they may be lost and shorten the genome. Elde studied the mechanism of the vaccinia virus, calling it a "genomic accordion."
For example, these changes may affect the interaction of the virus with the human immune system, weakening its defense capabilities. But trying to predict the effects of a specific mutation is like "bad weather forecasts," Elder said. "We have some patterns and some predictions, but we really can't stand because there is a weather system where a lot of variables rotate in all directions." Since they released the preprint in July, Drosten's lab has been studying viruses isolated from a Berlin patient who has deleted and copied the genes. The unpublished results are disturbing: "Cell cultures show obvious differences and replicate much faster," Drosten said. “We shouldn’t over-interpret this,” he warned, because the discovery in the lab doesn’t necessarily translate into the virus’s advantage in the real world. "But I found that this virus has shown differences in cell culture, which is worth noting." If the virus has a real-world advantage, but it does not continue to spread, then humans may be "just lucky," Jones said - "this time." He believes the current outbreak is a race between monkeypox virus and humans: "This virus is trying to adapt to humans, and humans are working to eliminate this virus," he said. "Who will have the upper hand?"
In the long run, I'll put my money on the virus. "Whatever happens next, the pandemic has provided researchers with an unexpected opportunity to see the evolution of poxvirus in real time. "We're all looking for clues, pieced together, and hopefully it's also an opportunity to drive scientific progress," Elder said. "But I support us, I support humanity. …I want to understand how these viruses work and then use this information so that we have some control over it.
——"Science"
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