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Juan Lama
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Scientists find relatives of rubella in bats, wild mice, and zoo animals. The virus that causes rubella, or German measles, finally has company. Scientists had never identified close relatives of the virus, leaving it as the only member of its genus, Rubivirus. But with a report in this week’s issue of Nature, rubella has gained a family. One of its two newfound relatives infects bats in Uganda; the other killed animals from three different species in a German zoo and was found in wild mice living nearby as well. The findings strongly suggest that at some point in the past, a similar virus jumped from animals to humans, giving rise to today’s rubella virus, the researchers say. Although neither of the new viruses is known to infect humans, the fact that a related virus jumped species raises concerns that the two viruses or other, as-yet-unknown relatives could cause human outbreaks. “We would be remiss not to be concerned, given what’s going on in the world today,” says epidemiologist Tony Goldberg of the University of Wisconsin, Madison, a senior author of the study. Highly infectious, the rubella virus usually causes rashes and fever, but in pregnant women it can lead to miscarriages, stillbirth, and babies born with congenital rubella syndrome, which includes deafness and eye, heart, and brain problems. An estimated 100,000 newborns are affected by the syndrome annually, mostly in Africa, the western Pacific, and the eastern Mediterranean; in many other countries the measles, mumps, and rubella (MMR) vaccine has made it a rarity. Goldberg and his former graduate student Andrew Bennett discovered one of the new viruses in apparently healthy cyclops leaf-nosed bats, netted at night in Kibale National Park in Uganda. They named it ruhugu virus, after the Ruteete region of Uganda and the local word for bat. The architecture of ruhugu’s genome is identical to that of the rubella virus, and 56% of the amino acids in its eight proteins matched those in rubella. The protein that interacts with the host’s immune cells was almost identical in both viruses. As they were getting ready to publish, the researchers learned that a team led by Martin Beer at the Friedrich-Loeffler Institute had detected another rubella relative in brain tissue from a donkey, a kangaroo, and a capybara—a giant rodent native to South America—that all died from encephalitis, an inflammation of the brain, at an unnamed zoo. They found the same virus in wild yellow-necked field mice caught in the zoo or within a 10-kilometer radius. The mice appeared to be fine, suggesting they were a natural reservoir from which the virus spilled over to the zoo animals. Comparing their data, the teams realized their viruses were related, although ruhugu was closer to rubella than the second relative, rustrela virus, named after a lagoon in the Baltic Sea. The teams decided to publish jointly. Two other viruses that primarily affect children, measles and mumps, also came from animals, Goldberg notes. “Now we know that every disease in the letters of the MMR vaccine has a zoonotic origin,” he says. Given the genetic distance between rubella and the ruhugu and rustrela viruses, the researchers don’t think either of them made the jump to humans—but they suspect they’ll find other Rubiviruses if they look closely. The paper is “really important because there’s very little understanding of where rubella came from,” says molecular anthropologist Anne Stone of Arizona State University, Tempe. “It was all by itself without any close relative.” The finding underscores the importance of the One Health approach, which recognizes that the health of people is closely connected to that of animals and the environment, she says. Both viruses bear close watching, researchers say. It’s “really interesting” that rustrela was able to infect both placental and marsupial mammals, and “was actively jumping between species,” says evolutionary virologist Edward Holmes of the University of Sydney. That flexibility could spell trouble, says vaccinologist Gregory Poland of the Mayo Clinic. “Who knows, if it could move from mice to other mammals, could it move to humans?” he asks. “In the end, the bugs win.” Study published in Nature (October 7, 2020): https://doi.org/10.1038/s41586-020-2812-9
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The second notable feature of SARS-CoV-2 is a predicted polybasic cleavage site (RRAR) in the spike protein at the junction of S1 and S2, the two subunits of the spike protein (Figure 1b)8,9. In addition to two basic arginines and an alanine at the cleavage site, a leading proline is also inserted; thus, the fully inserted sequence is PRRA (Figure 1b). The strong turn created by the proline insertion is predicted to result in the addition of O-linked glycans to S673, T678, and S686 that flank the polybasic cleavage site. A polybasic cleavage site has not previously been observed in related lineage B betacoronaviruses and is a unique feature of SARS-CoV-2. Some human betacoronaviruses, including HCoV-HKU1 (lineage A), have polybasic cleavage sites, as well as predicted O-linked glycans near the S1/S2 cleavage site. While the functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, experiments with SARS-CoV have shown that engineering such a site at the S1/S2 junction enhances cell–cell fusion but does not affect virus entry10. Polybasic cleavage sites allow effective cleavage by furin and other proteases, and can be acquired at the junction of the two subunits of the haemagglutinin (HA) protein of avian influenza viruses in conditions that select for rapid virus replication and transmission (e.g. highly dense chicken populations). HA serves a similar function in cell-cell fusion and viral entry as the coronavirus S protein. Acquisition of a polybasic cleavage site in HA, by either insertion or recombination, converts low pathogenicity avian influenza viruses into highly pathogenic forms11-13. The acquisition of polybasic cleavage sites by the influenza virus HA has also been observed after repeated forced passage in cell culture or through animals14,15. Similarly, an avirulent isolate of Newcastle Disease virus became highly pathogenic during serial passage in chickens by incremental acquisition of a polybasic cleavage site at the junction of its fusion protein subunits.... ...It is improbable that SARS-CoV-2 emerged through laboratory manipulation of an existing SARS-related coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for human ACE2 receptor binding with an efficient binding solution different to that which would have been predicted. Further, if genetic manipulation had been performed, one would expect that one of the several reverse genetic systems available for betacoronaviruses would have been used. However, this is not the case as the genetic data shows that SARS-CoV-2 is not derived from any previously used virus backbone17. Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in a non-human animal host prior to zoonotic transfer, and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage in culture could have given rise to the same observed features... Mandarin version of the article available at: http://virological.org/uploads/short-url/dHpDmgjWKLNlBztUWteEJZq4Pvw.pdf
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A team of scientists studying the origin of SARS-CoV-2, the virus that has caused the COVID-19 pandemic, found that it was especially well-suited to jump from animals to humans by shapeshifting as it gained the ability to infect human cells. Conducting a genetic analysis, researchers from Duke University, Los Alamos National Laboratory, the University of Texas at El Paso and New York University confirmed that the closest relative of the virus was a coronavirus that infects bats. But that virus's ability to infect humans was gained through exchanging a critical gene fragment from a coronavirus that infects a scaly mammal called a pangolin, which made it possible for the virus to infect humans. The researchers report that this jump from species-to-species was the result of the virus's ability to bind to host cells through alterations in its genetic material. By analogy, it is as if the virus retooled the key that enables it to unlock a host cell's door -- in this case a human cell. In the case of SARS-CoV-2, the "key" is a spike protein found on the surface of the virus. Coronaviruses use this protein to attach to cells and infect them. "Very much like the original SARS that jumped from bats to civets, or MERS that went from bats to dromedary camels, and then to humans, the progenitor of this pandemic coronavirus underwent evolutionary changes in its genetic material that enabled it to eventually infect humans," said Feng Gao, M.D., professor of medicine in the Division of Infectious Diseases at Duke University School of Medicine and corresponding author of the study publishing online May 29 in the journal Science Advances. The researchers found that typical pangolin coronaviruses are too different from SARS-CoV-2 for them to have directly caused the human pandemic. However, they do contain a receptor-binding site -- a part of the spike protein necessary to bind to the cell membrane -- that is important for human infection. This binding site makes it possible to affix to a cell surface protein that is abundant on human respiratory and intestinal epithelial cells, endothelial cell and kidney cells, among others. While the viral ancestor in the bat is the most closely related coronavirus to SARS-CoV-2, its binding site is very different, and on its own cannot efficiently infect human cells. SARS-CoV-2 appears to be a hybrid between bat and pangolin viruses to obtain the "key" necessary receptor-binding site for human infection. Original study published in Science Advances (May 29, 2020): https://doi.org/10.1126/sciadv.abb9153
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EcoHealth Alliance President Peter Daszak speaks with The Scientist about how pathogens like 2019-nCoV jump species, and how to head off the next pandemic. An outbreak of a new virus known as 2019-nCoV, which began in Wuhan, China, in December, has now sickened more than 900 people and killed at least 26. Efforts to contain the outbreak have caused major disruption in China, particularly in Wuhan and nearby cities, where authorities have stopped most forms of transportation. While researchers quickly identified and sequenced 2019-nCoV, many questions remain about the novel coronavirus, including which species first passed it to humans. The Scientist spoke with Peter Daszak, the president of the nonprofit EcoHealth Alliance and an infectious disease researcher who’s done extensive research on emerging viruses in China and elsewhere. He talked with us about how 2019-nCoV fits in with other coronaviruses, including the virus that causes SARS, and how future events might be prevented. Peter Daszak: There’s a lot being done on how coronaviruses infect people from animals, because we’ve had a few events where they’ve jumped from animals into people, including from livestock. So for MERS, we know the real key is to know what the host cell receptor is—that’s the protein on the surface of cells that viruses bind to and invade. So if we share the same cell surface receptor that the virus uses in bats or in camels or in pigs, then there’s a risk of that virus invading us. For SARS coronavirus, the cell surface receptor is called ACE2, angiotensin converting enzyme 2. We share that with bats, and [the virus] uses the same receptor [in bats and humans]. And . . . because this paper . . . just came out from the Wuhan [Institute of Virology] group, we now know that the new virus also uses that same surface receptor....
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