The Ebola Resurgence

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trader32176
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Re: The Ebola Resurgence

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Shape-shifting Ebola virus protein exploits human RNA to change shape

New study highlights VP40 as a promising therapeutic target

4/14/21


https://www.newswise.com/articles/shape ... pe?ta=home


Newswise — La Jolla, CA—The human genome contains the instructions to make tens of thousands of proteins. Each protein folds into a precise shape—and biologists are taught that defined shape dictates the protein’s destined function. Tens of thousands of singular shapes drive the tens of thousands of needed functions.

In a new Cell Reports study, researchers at La Jolla Institute for Immunology demonstrate how Ebola virus has found a different way to get things done. The virus encodes only eight proteins but requires dozens of functions in its lifecycle. The new study shows how one of Ebola virus’s key proteins, VP40, uses molecular triggers in the human cell to transform itself into different tools for different jobs.

“We’re all taught that proteins have ‘a’ structure,” says study co-leader Erica Ollmann Saphire, Ph.D., professor at La Jolla Institute for Immunology (LJI) and member of the LJI Center for Infectious Disease and Vaccine Research. “Ebola virus’s VP40 protein, however, changes itself into different structures at different times, depending on the function needed.”

VP40 is the protein that gives Ebola virus its distinctive string-like shape. Saphire’s previous studies showed that VP40 can take on a two-molecule, butterfly-shaped “dimer” or an eight-molecule, wreath-like “octamer” form.

There are dramatic rearrangements of the protein as it transforms from one to the other. The dimer is what physically constructs new viruses that emerge and release from infected cells. The octamer functions only inside the infected cell, in a controlling role, directing other steps of the viral life cycle.

The new study shows exactly what triggers these structural changes. The researchers found that VP40 senses and relies on particular human mRNA to make the transformation from the dimer to octamer.

Saphire worked with study co-corresponding author Scripps Research Professor Kristian Andersen, Ph.D. to deeply sequence RNAs captured and selected by VP40 inside cells. VP40 selected particular sequences, most often found in the untranslated tails of human mRNA.

Saphire lab postdoctoral fellows Hal Wasserman Ph.D. and co-first author Sara Landeras Bueno, Ph.D. , worked with purified VP40 in test tubes to get a glimpse of the dimer-to-octamer transformation in action. The duo tested many combinations of RNA molecules to try to trigger the transformation and found that particular human mRNA sequences rich in bases guanine and adenine were ideal for driving the same conformational change in vitro that they saw in high-resolution structures of VP40.

“We were very excited and surprised to see that the RNA that triggers this change comes from the host cell and not the virus,” says Landeras Bueno. “The virus is hijacking the host cell—this is another example of a virus acting like a parasite.”

Saphire says the study sheds light on the fundamentals of how information is encoded in the genome. There’s the genetic code, of course, but Ebola virus also controls how VP40 is deployed during different stages of its life cycle. “It has an additional layer of programming,” Saphire says.

The new study also offers further evidence that VP40 is a promising target for effective therapies. Because Ebola virus cannot spread without VP40, the virus is unlikely to acquire VP40 mutations that let it “escape” antibody therapies. This vulnerability has led the LJI team to think of VP40 as Ebola’s Achilles’ heel.

“VP40 fulfills an elaborate system of requirements for Ebola virus, so we don’t expect it to change much,” says Wasserman. “That means if we could attack VP40 specifically, the virus would be helpless.”

Wasserman says the octamer’s regulatory function is still slightly mysterious. The octamer is known to be essential to the Ebola virus life cycle, but more work needs to be done to understand how this VP40 structure controls Ebola virus replication.

Saphire is very interested in investigating whether other viruses—or living organisms—have proteins with the same “structural plasticity” as VP40. “I’ve always wanted to know if this kind of functionality is more common in biology than we think,” she says.

The study, “Cellular mRNA triggers structural transformation of Ebola virus matrix protein VP40 to its essential regulatory form,” was supported by the National Institutes of Health (grant P41 GM128577), the U.S. Department of Energy (contracts no. DE-AC02-06CH11357 and DE-AC02-76SF00515); and by the National Institutes of Health, National Institute of General Medical Sciences (grant P41 GM103393).

Additional study authors include co-first author Glenn Oliveira, Zachary L. VanAernum, Florian Busch, Zhe Li Salie and Vicki H. Wysocki.

DOI: 10.1016/j.celrep.2021.108986
trader32176
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Re: The Ebola Resurgence

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Rattling at the gates: Congo fends off new Ebola threat – but for how long?

The region held its breath when the haemorrhagic fever re-emerged this year. Confronting the spectre of Ebola during the Covid-19 pandemic is a terrifying prospect

4/15/21

https://www.telegraph.co.uk/global-heal ... st-africa/


In a hastily constructed Ebola treatment centre, Bertrand Karumba slowly peels off his protective gear, dipping it in disinfectant and laying it aside to be burned.

He knows that any hasty move could prove fatal. If a drop of virus goes in his eye or his mouth, he could end up like the patients he’s spent the last few years mopping up.

“I’ve seen friends die,” the sinewy hygienist told the Telegraph, in the ramshackle city of Butembo in the east of the Democratic Republic of the Congo.

“I was in the last outbreak from 2018 to 2020. We were so overjoyed when it was over. But when I heard Ebola was back, I came straight back to fight it.”

By mid-February, alarm bells were ringing across Africa.

Billions of pounds had been spent and thousands of lives lost trying to eradicate the deadly disease. For a while, it seemed like victory was at hand – but suddenly, the haemorrhagic fever was back, rattling at the gates.

On February 7, the Democratic Republic of Congo declared a new Ebola outbreak in North Kivu province, an isolated eastern region studded by a dizzying array of machine-gun-toting armed groups.

A week later and thousands of miles away, the west African nation of Guinea declared another outbreak in a cross-border trading area, which fended off the most deadly Ebola outbreak in history five years ago.

Healthcare workers who had seen their family members and colleagues die from the highly infectious disease were bewildered. Why was the death sentence disease back? And how could they beat back the two outbreaks while the coronavirus pandemic sucked up the world’s cash and energy?

“We worked so hard for two years to stop the last Ebola outbreak. Then coronavirus and Ebola came at the same moment. It’s very stressful,” said Unicef psychologist Odette Kahindo Sikuli earlier this month.

But a little more than a month after both countries raised the alarm, the tide seems to have suddenly turned.

All those infected with Ebola in Congo have either died or have been discharged from treatment, and no new cases have been recorded for more than three weeks.

Guinea has two active cases. But it has not seen the mad rush of infections many feared.

The sudden containment of the outbreaks in these locations is a relief to everyone. In the past, Ebola has been utterly devastating and taken years to get under control.

From 2013 to 2016, the virus tore through Guinea, Sierra Leone and Liberia’s tattered healthcare systems, killing at least 11,300 people. Then from 2018 to 2020, the disease killed more than 2,200 people in Eastern Congo, where Ebola workers faced massive community resistance, mobs of Ebola-deniers and armed groups.

But this time, both countries now seem to have contained the outbreaks with a sum total of 32 recorded cases and 15 deaths between them.

Now a countdown of 42 days has begun in Congo. If no cases are reported in that time, the outbreak will be declared over – a triumph for humanity at a time when Covid-19 is still killing millions.

Experts have put the initial success down to the major advances in Ebola detection, control and treatment which have been made over the last few years.

In 2018 and 2019, the world’s first Ebola vaccine was hailed as a game-changer and administered en masse in two outbreaks in Congo.

“Sadly, six people have lost their lives, and 11 others were infected, but we’ve come a long way from previous outbreaks that affected so many more lives,” said Dr Medard Onobaiso, chief of Unicef’s Beni field office in Eastern Congo.

Dr Onobaiso said that efforts of community health workers to trace and vaccinate the contacts of anyone infected and also the legacy of the massive Ebola vaccination campaign, which took place during the last epidemic, were key reasons for the current containment.

More than 15,000 vaccines were sent to Eastern Congo’s Nord Kivu province and over 1,500 shots administered to contact cases in the first few weeks, Dr Soce Fall, deputy head of Emergency Response at the WHO, told the Telegraph.

The task is immense – about 100 contact cases are vaccinated for every positive case, says Dr Fall.

The Ebola vaccine had not been developed when west Africa fought Ebola. So there is no mass immunity to disease in the population around Guinea’s outbreak.

But a rapid drive by the WHO and the Guinean government to vaccinate frontline staff and all the people who’d come into contact with those infected seems to have help to stop the epidemic in its tracks.

Within days of Guinea announcing its Ebola outbreak some 30,000 doses had been flown to the country and now some 3,000 people have been vaccinated, with surveillance ramped up in case of transmission across the highly porous borders into Sierra Leone and Liberia.

But optimism that the latest outbreaks have been squashed comes as new research that experts have described as “genuinely shocking” suggests the virus can linger in survivors for years.

There are three ways someone can catch Ebola. First, it can be transmitted from animals like bats to humans. Zoonotic transmission, as this form of transmission is known, was behind west Africa’s devastating Ebola outbreak in 2013.

Secondly, it can be caught from the bodily fluids of an infected person, such as saliva, blood or semen. And thirdly, it can be transmitted from someone who has recovered from the disease but still harbours in parts of their body that are protected from the body’s immune response.

But recent genome sequencing of Ebola samples shows that both Congo and Guinea’s outbreaks may have been sparked by survivors from the countries’ previous outbreaks.

Researchers have known for several years that Ebola could live on for more than a year in survivors who can potentially transmit the disease.

In 2016, researchers in Guinea found that one man who had survived Ebola had carried the virus in his testes for more than 500 days and had gone on to infect his sexual partner. But no one had any idea that someone could hold onto the virus for five years.

This means that there could be a significant ‘human reservoir’ of cases in the communities around the outbreaks.

This means that while major advances have been made fighting the disease and nipping the bud of evolving epidemics, Ebola outbreaks could become far more common.

“It's...really troubling as a human being who is well aware of the painful stigmas already faced by many survivors. And the implications for controlling Ebola are extremely worrisome,” says Dr Angela Rasmussen of Georgetown University.

Health experts say that there needs to be a radical change in how the world manages the disease – there needs to be a shift from reacting quickly to outbreaks, to preventive vaccination campaigns.

“We need to continue investing in research and development for Ebola, including on vaccines. We are halfway. We cannot just stop. In the future, we need to move to a more preventative measure. If we don’t it will have a catastrophic impact on global health,” said Dr Fall.

“We're changing the paradigm in approaching the new resurgences, and by using preventive care, and also a vaccination for contact cases,” said Dr Ki-Zerbo. “So we're at the outset of a new era.”
trader32176
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Re: The Ebola Resurgence

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Outbreak Brief 9: Ebola virus disease (EVD) Outbreak

20 April 2021


https://africacdc.org/disease-outbreak/ ... -outbreak/


Outbreak Update:
Since the 13th of April 2021, no new cases or deaths from Ebola virus disease have been reported in Guinea and Democratic Republic of Congo. Cumulatively there has been 35 cases of Ebola virus disease, including 18 deaths (CFR: 51%), and 15 recoveries from the Democratic Republic of Congo (12 cases; 6 deaths; 6 recoveries) and Guinea (23; 12; 9). These include two health workers from the Democratic Republic of Congo and five health workers from Guinea. See Table 1 for the subnational details.
● Updates from the Democratic Republic of Congo: The last confirmed case was reported 50 days ago. The outbreak will be declared over if there are no new cases reported over the next 13 days.
● Updates from Guinea: The last confirmed case and death reported was reported 17 days ago.
trader32176
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Re: The Ebola Resurgence

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UTMB researchers receive $11.3 million grant to study immunopathogenesis of Ebola

5/7/21

https://www.news-medical.net/news/20210 ... Ebola.aspx


Researchers at the University of Texas Medical Branch at Galveston have been awarded an $11.3 Million, multi-year grant from the National Institute of Allergy and Infectious Diseases to study immunopathogenesis of Ebola, and in particular to determine why cells infected with Ebola develop "immune system paralysis," which inhibits immune response, leads to hyperinflammation, and allows the deadly infection to spread. The research will be led by Co-Principal Investigators Alexander Bukreyev, PhD, of UTMB's Department of Pathology, and Mariano Garcia-Blanco, MD, PhD, Chair of the Biochemistry and Molecular Biology Department.

While some might question, "Why Ebola now?" Dr. Bukreyev explains that, while the COVID-19 pandemic has grabbed headlines and been a primary focus for researchers worldwide for the last 18 months, scientists at UTMB have never stopped working to increase their understanding of Ebola as part of a global effort to develop effective medical countermeasures against a virus with an average case fatality rate of as much as 50 percent, according to the World Health Organization (WHO).

" There have been two Ebola outbreaks going on in Africa this year, and this disease remains one of the deadliest known to humans. With COVID-19 we have seen how easily an infectious disease can originate in one location and spread around the world. The same is true with more deadly viruses, as well, and for that reason, research on Ebola that will help us develop effective vaccines and therapies has never stopped at UTMB."

- Alexander Bukreyev, PhD, Co-Principal Investigator, UTMB's Department of Pathology

Research on live Ebola virus must take place inside of a Biosafety Level 4 (BSL4) laboratory at the Galveston National Laboratory. BSL4 labs are built with specially designed air handling and waste systems, and scientists who work in BLS4 labs further protect themselves by wearing spacesuits that are connected by a hose to breathing air. It is in this environment that the team will investigate Ebola infections in human cell culture and in nonhuman primates.

"There are very few places in the world where this type of medical research can take place, and while our focus will be on Ebola, this work will have important implications for other severe acute viral infections that share mechanisms with Ebola, such as Marburg virus, Lassa virus and SARS-CoV-2, which causes COVID-19," Garcia-Blanco said.

The research, which will take place over five years, will also involve the development of sophisticated models using 'big data' that can be manipulated to predict infection outcomes and pathogenicity. The multi-disciplinary project will result in a comprehensive understanding of how Ebola infections take hold, with the goal of developing new insight into effective prevention and treatments against the deadly disease.

The UTMB team also includes Ricardo Rajsbaum, PhD, and Thomas Geisbert, PhD, from the Department of Microbiology & Immunology and Andrew Routh, PhD, from the Department of Biochemistry and Molecular Biology. Additional collaborators include Ivan Marazzi, PhD, and Stuart Sealfon, MD, of the Icahn School of Medicine at Mount Sinai Hospital, and Dr. Matt Weirauch, PhD, of Cincinnati Children's Hospital.

Source:


University of Texas Medical Branch at Galveston
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