Model Monday's: Diana Moldovan
Bird Flu Is Just FOUR Mutations Away From Causing Human Outbreak — As Experts Describe Virus As 'pandemic Threat That's Going To Keep Knocking At Our Door'
Bird flu is just four mutations away from being able to jump to humans and cause a pandemic, experts warn.
The virus has been given ample opportunity to spread in recent years as it rampages across the world's bird and mammal population.
Each time it begins replicating in a new host it earns another chance to mutate and potentially gain one of these deadly traits.
Some mutations it could gain that cause it to pose a risk to humans includes the ability to survive in the air and optimizing itself to infect human cells.
Experts highlight four key traits bird flu can pick up through mutation that can lead to it causing a pandemic level event in humans. Two of the mutations would need to occur on the hemagglutinin, the outside parts of the virus that are responsible for binding it to human cells. With these mutations it can travel through the air and bypass the body's natural defenses. Other changes include matching itself to better connect to human viruses rather than bird, and to optimize itself to strike cell proteins
Dr Mathilde Richard, a virologist at the Erasmus Medical Center in the Netherlands, told the journal Science: 'This is the threat that's going to keep knocking at our door until it will indeed, I assume, cause a pandemic.
'Because there is no way back.'
Before the virus can cause any harm to humans, it will first need to reach them.
Currently, a person can be infected with bird flu after viral particles enter their body through the mouth, nose or eyes.
Usually, this happens when someone touches an infected surface and then wipes their face.
These instances are rare, though, with only around 1,000 cases ever having been detected in humans.
In a landmark 2012 study, Dutch researchers manufactured the H5N1 bird flu to spread airborne between ferrets.
This type of research falls under the controversial 'gain-of-function' label and has been restricted in most of the world.
But through their studies, the team identified changes to the virus's bindings that allow it to travel through the air and attach to human cells, it's RNA code and that allow it to infect more efficiently and let it escape natural barriers.
Viral pathogens, such as COVID-19, the flu and respiratory syncytial virus transmit most effectively through the air.
But, bird flu has trouble spreading through aerosol particles.
Like other pathogens, the avian flu attaches to a host's cell through a part called the hemagglutinin. These are small proteins on the outer layer of the virus.
When the virus infects an animal's cell, the hemagglutinin fuses with liquid in the cell called the vesicle.
It fuses with it because of the high acidity of the liquid. This allows the virus to melt into the cell and infect the membrane — an inner layer of cell protection.
Once in the membrane, the virus can cause harm to the cell with little resistance, fully infecting it and further transmitting itself when it starts to replicate.
Because water and other surfaces have a relatively balanced pH, the virus can survive on surfaces for long periods of time.
But, it is a different story when it travels through the air after a person sneezes or coughs out particles.
Carbon dioxide in the air causes it to become slightly acidic. As a result, the hemagglutinin will begin to melt and fail to reach a new host.
Scientists say that if the hemagglutinin of bird flu mutates to be more similar to that of Covid or influenza, it will be able to travel through the air.
Once the virus reaches the host, it then must infect them.
The second mutation optimizes the flu to bind to a human cell.
Birds fall into the 'aves' class within the animal kingdom, while humans are considered mammals.
This means they have different biologic makeup, enough that virus's tailored for the animals have trouble with humans.
Avian flu has mutated to optimize itself infect birds and as a result, has a hard time finding non-avian hosts. The virus was first detected in ducks in Europe and Asia, but it is unclear where they picked it up.
But, this could change with simple mutations of the hemagglutinin. A more optimized hemagglutinin would convert more exposures into infections, leading to sharp growth in cases.
Changes to amino acids dubbed the G228S and Q226L will be necessary for this optimization to occur, scientists say after reviewing data from previous outbreaks.
When these amino acids undergo this mutation, they are better adapted to attach to carbohydrates in human cells.
These mutations were detected in previous human outbreaks of the virus.
This includes the 1968 H3N2 outbreak, which originated in America and ended up killing around 1million people worldwide.
The 1957 'Asian flu' outbreak was responsible for 1.1million deaths globally.
Later, it was determined to be caused by the H2N2 strain of bird flu, which also had these mutations.
Both strains of the virus have since vanished from the human population, but their outbreaks show these dangerous mutations are possible.
It is thought the woman caught the virus from a wet market where she spent time before becoming ill, after samples taken from the market tested positive for influenza A(H3)
The woman, from the Guangdong province, first became ill on February 22. She was admitted to the hospital with severe pneumonia on March 3 and died on March 16
The hemagglutinin is not the only part of the virus that would need to change.
The third mutation, which scientists believe is the most important evolution a strain of the bird flu would need to undergo to pose a threat to humans, is within its RNA.
All influenza viruses consist of single-stranded RNA as opposed to dual-stranded DNA.
RNA is made up of four base chemicals: cytosine, guanine, adenine and uracil. In DNA, thymine is present instead of uracil.
Every combination of three chemicals within the chain of RNA forms an amino acid.
These acids are the building blocks of protein, and their combination make up a multitude of traits.
Unlike a cell, viruses do not have both DNA and RNA present. A majority of infectious diseases gain their traits from their RNA makeup.
Each trio of these chemicals on a chain of RNA make up a chemical responsible for proteins that assist in bodily functions.
If the cytosine in some of these chains instead mutates to adenine, it will change the output of some strains from a chemical called glutamine to one known as lysine.
Scientists have dubbed this the E627K mutation. When glutamate is swapped out for lysine, the virus can more infect a person's protein cells than a bird's cells.
With these three mutations, the virus will likely be able to pose a threat to humans.
But, with a fourth change it could bypass the final defenses humans have and start a deadly pandemic.
The myxovirus resistance gene A (MxA) is a protein in human cells built to destroy RNA viruses like the bird flu.
When viral RNA is detected in the cell the protein is triggered. It most cases, it can break the pathogen's binding and prevent infection.
When it cannot, it signals to the immune system that there is an invader and triggers a flow of white blood cells to fight the virus.
The MxA is more sensitive in humans than other mammals, making it harder for the bird flu to cause an outbreak in us than it would be in foxes, sea lions and others who have suffered from the infection over the past two years.
While Dr Richard says that the virus will inevitably reach the point where all four mutations have occurred and it can strike humans, the time it could take for this varies greatly.
Because of the randomness of genetic mutation and the very specific changes the virus needs, it could be decades before even a single one of the changes are made.
For now, the bird flu remains a threat that humans are observing but are not particularly worried about.
Human cases do spring up on occasion, though. Officials reported that a 56-year-old woman in southeast China died from the H3N8 strain of the virus in March.
The strain she suffered from is poorly tailored for humans, though. Only three case of the H3N8 strain in humans has even been reported.
The strain that poses the most threat to humans is the H5N1 virus.
That strain has been recorded around 870 times since it was first discovered in 1959, killing around half of patients.
It has rampaged across the world's wild bird population over the past two years, and caused scattered infections among humans.
Unlike other strains of the bird flu, it has shown that in can spread human-to-human.
Transmission between people was confirmed during a 1997 Hong Kong outbreak that stuck 18 people.
Omicron Spike N679K Mutation Acts As A Loss-of-function Mutation Attenuating SARS-CoV-2 In Vitro & In Vivo
In a recent study posted in the bioRxiv* preprint server, researchers explored the impact of a loss-of-function mutation in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants on the expression of the spike protein.
Study: Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection. Image Credit: JuanGaertner/Shutterstock.Com
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Several SARS-CoV-2 variants of concern (VOCs) with diverse spike protein mutations have emerged since the coronavirus disease 2019 (COVID-19) pandemic began.
The spike (S) protein on virions comprises three subunits, known as a trimer. These subunits are called S1 and S2. Omicron studies have primarily concentrated on the receptor-binding domain (RBD) and its effect on infection- or vaccine-induced immunity due to the numerous mutations present in the spike protein.
Mutations near the S1/S2 cleavage site and furin cleavage site (FCS) are known to contribute to the evolution of SARS-CoV-2, but their impact on Omicron has not been extensively researched.
About the studyIn the present study, researchers assessed how the SARS-CoV-2 Omicron C-terminus of the S1 subunit (CTS1) mutations impact SARS-CoV-2 pathogenesis and infection.
A mutant SARS-CoV-2 with N679K, P681H, and H655Y mutations was created in the WA1 backbone (YKH). Spike processing in purified virions from wild-type (WT) and YKH infection was evaluated. The team hypothesized that N679K could affect SARS-CoV-2 infection.
A SARS-CoV-2 mutant with only an N679K mutation in the WA1 backbone was creat to assess this. The study involved infecting three- to four-week-old golden Syrian hamsters with N679K and noting weight loss and disease progression for seven days.
The team determined the cause behind the loss of function seen in the N679K mutant. The effects of N679K on proteolytic spike processing were evaluated, considering its location next to the FCS. Spike processing was examined by blotting purified virions from N679K, WT, and Omicron variant BA.1.
ResultsThe YKH mutant produced smaller plaques than the WT strain. The YKH mutant displayed no reduction in stock titers or replication kinetics within Vero E6 cells compared to the SARS-CoV-2 WT strain.
The endpoint titers associated with YKH were higher at 48 hours post-infection (hpi) in Calu-3 2B4 cells in comparison to WT, although replication was decreased at 24 hpi. The study indicated that the three mutations might influence the Omicron variant's infection dynamics, potentially providing some benefits.
The YKH spike protein underwent more processing than the WT spike protein, similar to Omicron and Delta. At 24 hpi, the YKH spike had an S1/S2 cleavage ratio to a full-length spike ratio of approximately 2.4:1, while the WT had similar levels of S1/S2 product as full length.
The YKH mutant, which contains the H655Y, N679K, and P681H mutations, led to higher viral endpoint yields within human respiratory cells and played a role in the improved spike processing of Omicron.
The N679K plaque sizes were smaller at two and three days post-infection (dpi) compared to WT, and stock titers were negligibly lower according to the initial characterization. The observed variations in plaque size and stock titers align with previous findings on most Omicron strains.
The N679K mutant showed reduced replication in Calu-3 2B4 and Vero E6 cells at 24 hpi, in contrast to the minimal differences observed in YKH replication kinetics. The study found that N679K viral titer recuperated by 48 hpi; the mutation appears to be a loss-of-function for replication in both cell lines.
N679K-infected hamsters showed less body weight loss in comparison to WT-infected hamsters. The study found that despite significant weight loss, the N679K viral titers detected in the lung samples were similar to the wild type at two and four days dpi.
At two dpi, the N679K mutant virus showed similar viral titers to the wild-type virus in nasal washes. However, at four dpi, the mutant virus exhibited decreased replication compared to the wild-type virus.
The study suggests that the N679K mutation includes a loss-of-function phenotype both in vitro and in vivo. The researchers hypothesize that the effect of the P681H and H655Y mutations may mitigate this loss of function.
N679K exhibited a 66% lower S/N ratio than WT, indicating a greater decline in spike protein relative to the decrease in purified virions. The study found that Omicron's S/N ratio decreased similarly, suggesting that the phenotype remains consistent despite all Omicron mutations. The N679K mutation leads to lower levels of the Omicron spike protein than the WT.
ConclusionThe study findings showed that the Omicron N679K mutation leads to consistent loss of function in subvariants. The N679K mutation reduces the virus's strength both in vitro and in vivo by enhancing spike degradation.
The amplifying effects of other Omicron mutations, such as H655Y and P681H on spike processing and infection may offset the N679K mutation's weakening effect.
The reduced spike protein expression caused by N679K could impact immunity resulting from vaccines and infection. Further research is needed to clarify the significant impact of the Omicron CTS1 mutations on SARS-CoV-2 infection.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
The Role Of Mutation In Nucleoproteins Of SARS-CoV-2
Scientists from The Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences, together with foreign colleagues, have demonstrated that human 14-3-3 proteins, which are known for their role in replication of many viruses, bind differentially with more often mutating regulatory parts of nucleoproteins (N protein) of the SARS-CoV-2 virus.
Presumably, the result of this correlation changes both the virus life cycle and 14-3-3-dependent cell functions. The interaction force of the 14-3-3 and N protein is greatly influenced by mutations in the particular parts of the latter, and the results of the research, published in the Journal of Molecular Biology, may be useful in drug discovery against new strains of coronavirus.
Nucleocapsid protein (nucleoprotein or N protein) is common for single-stranded RNA-viruses, including coronaviruses, and is responsible for replication, packaging and storage of viral genome. Its structure has a central regulatory part, consisting of about 30 amino acid residues (mainly the residues of serine and arginine, the so-called SR-rich region), where special cellular enzymes transfer phosphate groups from molecules of ATP (phosphorylate them).
Such modifications trigger human 14-3-3 proteins to bind N-protein. 14-3-3 proteins participate in a range of crucial cell processes: they regulate the activity of the protein partners, their intracellular distribution, and their interaction with each other, thus becoming involved in the regulation of cell cycle, metabolism, gene activity, and cell death (apoptosis).
"In our previous work, we demonstrated that 14-3-3 proteins recognize the nucleocapsid protein of SARS-CoV-2, and we were able to determine the precise area of their interaction. Now we decided to check whether other similar areas in N protein exist," explains Kristina Tugaeva, the first author of the work, the member of the group "Protein-protein interaction" of the Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences.
This task is important since the 14-3-3-binding part of N protein is located in the SR-rich region, which is a hotspot of viral mutations. In the case of S protein, the consequences of mutations seem obvious: They make virus entry into the cell easier or help evade the immune system, whereas the effects of mutations in N protein remain mainly unknown, in spite of the fact that N protein is the main factor of pathogenicity.
The authors found that 14-3-3 proteins site-selectively recognize to either of two phosphorylated pseudo-repeats in the SR-region of the SARS-CoV-2 nucleoprotein: centered at Ser197, identified earlier, and a new site, centered at Thr205. Interestingly enough, the binding force (affinity) of the second area turned out to be tighter for all members of the 14-3-3 family.
Structural insights led to the conclusion that the Ser197 and Thr205 residues in the N protein are located too close to each other to allow 14-3-3 to bind both. Thanks to the interaction with 14-3-3, the regulatory SR-region of the N protein could be protected from cell enzymes that can influence the cell life cycle by removing phosphate groups.
"So we suggested that mutations in the N protein of the coronavirus affect the binding efficiency of 14-3-3. Moreover, precisely those disordered regions especially sensitive to mutations play a role in this interaction. The results of our new research could contribute to the discovery of drugs against new strains of coronavirus," concludes Kristina Tugaeva.
More information: Kristina V. Tugaeva et al, Human 14-3-3 Proteins Site-selectively Bind the Mutational Hotspot Region of SARS-CoV-2 Nucleoprotein Modulating its Phosphoregulation, Journal of Molecular Biology (2022). DOI: 10.1016/j.Jmb.2022.167891
Provided by Russian Foundation for Basic Research
Citation: The role of mutation in nucleoproteins of SARS-CoV-2 (2023, April 25) retrieved 30 April 2023 from https://phys.Org/news/2023-04-role-mutation-nucleoproteins-sars-cov-.Html
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