Viruses remain a significant cause of human disease and death, most notably illustrated through the current Covid-19 pandemic. Control of virus infection continues to pose a significant global health challenge to the human population. Viruses can spread through multiple routes, including via environmental and surface contamination where viruses can remain infectious for days. Methods to inactivate viruses on such surfaces may help mitigate infection. Now, Stephen Bell and colleagues presented evidence identifying a novel ‘virucidal’ product in Rosin soap, which is produced from Tall oil from coniferous trees. They showed that Rosin soap was able to rapidly and potently inactivate influenza virus and other enveloped viruses like SARS-CoV-2. Their study recently appeared in BioRxiv.
To determine whether Rosin Soap Powder could reduce the infectivity of influenza virus (IAV WSN strain), they performed an experiment, in which they incubated influenza virus stocks with rosin acid (2.5% w/v) at 37°C for 5-30 minutes and measured residual infectivity. This experiment revealed that the incubation of IAV with Rosin Soap Powder gave at least a ten-thousand-fold reduction in infectivity.
Next, they hypothesized that, the Rosin soap can also inhibit other viruses. So, they investigated the virucidal activity of Rosin soap against enveloped viruses like IAV strain (H3N2, Udom), RSV, SARS-CoV-2 and non-enveloped encephalomyocarditis virus (EMCV). They carried out same protocol as they used for IAV and measured residual viral activity using specific-specific means. Conditions for these experiments were room temperature for 5 minutes. They found that, all enveloped viruses were inhibited by Rosin soap, demonstrating that the activity of rosin soap is not limited to IAV or WSN. However, this soap cant able to inhibit the non-enveloped EMCV. The susceptibility of enveloped viruses to Rosin acids (and not the non-enveloped virus) suggested that the viral lipid membrane is a major target of inactivation.
Finally, in order to determine whether the virucidal activity of Rosin soap is dependent on concentration or not. They performed experiment with different concentration (2.5, 0.25 and 0.025%) together with varying incubation time (5, 15 and 30 mins) and incubation temperature (37°C). They demonstrated that the virucidal activity of Rosin soap was only dependent on concentration. Meaning, 2.5% concentration provide complete inhibition of viruses and reduction in concentration leads to reduction in inhibition of viruses.
Finally, they demonstrated that, in constrast to concentration, virucidal activity of this soap was completely independent of incubation time and temperature.
“This novel chemical inactivation method against enveloped viruses, could be of great use in preventing virus infections in certain settings.”
— they concluded.
Reference: Stephen Bell, Derek J Fairley, Hannele Kettunen, Juhani Vuorenmaa, Juha Orte, Connor G G Bamford, John McGrath, “Rosin Soap Exhibits Virucidal Activity”, bioRxiv 2021.07.19.452918; doi: https://doi.org/10.1101/2021.07.19.452918
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Immunologists at McMaster University have discovered a previously unknown mechanism which acts like a spider web, trapping and killing pathogens such as influenza or SARS-CoV-2, the virus responsible for COVID-19.
The researchers have found that neutrophils, the most abundant white blood cells in the human body, explode when they bind to such pathogens coated in antibodies and release DNA outside of the cell, creating a sticky tangle which acts as a trap.
The discovery has implications for vaccine design and delivery, including aerosol and nasal spray technologies that could help the body head off infections before they have a chance to take hold.
“Vaccines can produce these antibodies that are present in our lungs, which are the first type of antibody to see viruses like flu or COVID-19, which infect our lungs and respiratory tracts,” says the study’s lead author Matthew Miller, an associate professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research and Canada’s Global Nexus for Pandemics and Biological Threats. “Mechanisms that can stop the infection at the site where it enters our body can prevent the spread and serious complications.”
By comparison, injectable vaccines are designed to bolster antibodies in the blood, but those antibodies are not as prevalent at the sites where infection begins.
“We should be thinking carefully about next generation COVID-19 vaccines that could be administered in the respiratory tract to stimulate antibodies. We don’t have many candidates right now that are focused on raising the mucosal response,” says Hannah Stacey, a graduate student in the Miller Lab and lead author of the paper, who recently won a major national scholarship from the Canadian Society for Virology for her work on COVID-19.
“If you want a lot of these antibodies that are really abundant in blood, then injections make the most sense, but if you want antibodies that are abundant in the respiratory tract, then a spray or an aerosol makes sense,” she says.
Researchers caution that while the body’s spider-web mechanism has the potential to be hugely beneficial, it can cause harm too, including inflammation and further illness when the web formation is uncontrollable.
They point to the early waves of the pandemic, prior to vaccinations, when these NETs, or neutrophil extracellular traps, were found in some patients’ lungs, and had made their breathing more difficult.
“An immune response that is meant to protect you can end up harming you if it’s not properly controlled,” says Miller. “It’s important to understand the balance of the immune system. If you have a lot of these antibodies before you get infected, they are likely going to protect you, but if the infection itself stimulates a lot of those antibodies it might be harmful.”
Electrical and computer engineers take on complex modeling questions that can further our understanding of virus spread in small spaces.
How long do virus-laden particles persist in an elevator after a person infected with COVID-19 leaves? And is there a way to detect those particles? A group of electrical engineers and computer scientists at KAUST set out to answer these questions using mathematical fluid dynamics equations.
“We found1 that virus-laden particles can still be detected several minutes after a short elevator trip by an infected person,” says KAUST electrical engineer Osama Amin.
The team’s equations and breath simulations suggest that a biosensor’s ability to detect a virus improves when placed on an elevator wall that can reflect particles. Also, to protect future occupants, the amount of particles in the air can be reduced by making the other three walls absorptive.
Amin and his colleagues at KAUST have been working on developing a nontraditional communication concept called “communication via breath.” The concept2 models chemical and biological molecules emitted in exhaled breath as if they are information carriers in a communication system that can be detected on the other end by a “receiver,” in this case a biosensor.
“This kind of study requires input from researchers with varied expertise in theoretical channel modeling, system design and integration, and machine learning schemes,” says Amin.
In their previous work, they used equations to understand how exhaled molecules disperse in open spaces3. They also proposed4 a sensing system that can detect molecules exhaled from people’s breath at mass gatherings.
In their current work, they developed a model and simulations that describe what happens to molecules exhaled in breath within a closed room over space and time. Their modeling took into consideration the abilities of walls to absorb or reflect particles. Once their models were able to describe, solve and simulate virus-laden particle concentration in a small room over space and time, the researchers worked on calculating the probability of a biosensor being able to detect those particles.
The calculations assumed the deployment of a biosensor that uses antibodies to bind to a specific virus and initiate a signal. They also accounted for parameters such as aerosol sampling time and volume, sampling efficiency and the probability of the antibodies binding to a virus.
“Our study provides vital mathematical and simulation gears for our leading research on communication via breath, which we hope will be used for more analyses and system designs,” says KAUST computer scientist Basem Shihada.
The team is now developing an aerosol sampling and detection prototype for organic chemicals exhaled in breath. “We also plan on proposing mechanisms that reduce the probability of infection in small spaces, including ventilation mechanisms, periodical air sanitization and the design of absorptive and reflective walls,” says Shihada.
An international team of researchers have shed new light on the early stages of viral evolution.
The team say their findings have implications for the treatment of viruses in future.
Researchers from the Universities of York and Leeds, collaborating with the Hilvert Laboratory at the ETH Zurich, studied the structure, assembly and evolution of a ‘container’ composed of a bacterial enzyme.
The study – published in the journal Science– details the structural transformation of these virus-like particles into larger protein ‘containers’.
It also reveals that packaging of the genetic cargo in these containers becomes more efficient during the later stages of evolution. They show that this is because the genome inside evolves hallmarks of a mechanism widely used by natural viruses, including Covid-19, to regulate their assembly.
That mechanism was a joint discovery of the York and Leeds team. Professor Reidun Twarock, from the University of York’s Departments of Mathematics and Biology, and the York Cross-disciplinary Centre for Systems Analysis, said: “Using a novel interdisciplinary technique developed in our Wellcome Trust-funded team in Leeds and York, we were able to demonstrate that this artificial system evolved the molecular hallmarks of a ‘virus assembly mechanism’, enabling efficient packaging of its genetic cargo.”
In its evolution, the artificial virus-like particle efficiently packages and protects multiple copies of its own encoding messenger RNA.
Professor Peter Stockley from the University of Leeds’ Astbury Centre for Structural Molecular Biology, said “What’s remarkable is this artificial virus-like particle evolves to be more efficient in packaging RNA. Our collaboration shows that following the evolutionary steps the encapsidated messenger RNAs incorporate more Packaging Signals than the starting RNAs. In other words, the phenomenon we have been working on in natural viruses “evolves” in an artificial particle, and the results in this paper therefore describe a process that may have occurred in the early evolution of viruses. This understanding enables us to exploit these containers as delivery vehicles for gene therapeutic purposes.”
About this research
Researchers from the Universities of York and Leeds collaborated with the Hilvert Laboratory at the ETH Zurich to study the virus-like particles.
Featured image credit: ETH Zürich / Stephan Tetter
Reference: Rebecca Chandler-Bostock, Carlos P. Mata, Richard J. Bingham, Eric C. Dykeman, Bo Meng, Tobias J. Tuthill, David J. Rowlands, Neil A. Ranson, Reidun Twarock, Peter G. Stockley. Assembly of infectious enteroviruses depends on multiple, conserved genomic RNA-coat protein contacts. PLOS Pathogens, 2020; 16 (12): e1009146 DOI: 10.1371/journal.ppat.1009146
An important step in the battle against antibiotic-resistant bacteria
The battle against antibiotic-resistant bacteria: A new study at Tel Aviv University revealed a mechanism through which “good” viruses can attack the systems of “bad” bacteria, destroy them and block their reproduction. The researchers demonstrated that the “good” virus (bacteriophage) is able to block the replication mechanism of the bacteria’s DNA without damaging its own, and note that the ability to distinguish between oneself and others is crucial in nature. They explain that their discovery reveals one more fascinating aspect of the mutual relations between bacteria and bacteriophages and may lead to a better understanding of bacterial mechanisms for evading bacteriophages, as well as ways for using bacteriophages to combat bacteria.
The study, published recently in PNAS – Proceedings of the National Academy of Sciences, was led by Prof. Udi Qimron, Dr. Dor Salomon, Dr. Tridib Mahata and Shahar Molshanski-Mor of the Sackler Faculty of Medicine. Other participants included Prof. Tal Pupko, Head of the Shmunis School of Biomedicine and Cancer Research and also of the new AI and Data Science Center ; Dr. Oren Avram of the George S. Wise Faculty of Life Sciences; and Dr. Ido Yosef, Dr. Moran Goren, Dr. Miriam Kohen-Manor and Dr. Biswanath Jana of the Sackler Faculty of Medicine.
Prof. Qimron explains that the antibiotic resistance of bacteria is one of the greatest challenges faced by scientists today. One potential solution may lie in further investigation of the targeted eradication of bacteria by “good” bacteriophages; namely, understanding bacteriophage mechanisms for taking over bacteria as a basis for the development of new tools to combat bacterial pathogens.
With this intention in mind, the current study unveiled the mechanism by which the bacteriophage takes control of the bacteria. The researchers found that a bacteriophage protein uses a DNA-repair protein in the bacteria to “cunningly” cut the bacteria’s DNA as it is being repaired. Since the bacteriophage’s own DNA has no need for this specific repair protein, it is protected from this nicking procedure. In this way the “good” bacteriophage does three important things: it distinguishes between its own DNA and that of the bacteria, destroys the bacteria’s genetic material, and blocks the bacteria’s propagation and cell division.
Prof. Qimron adds: “The bacteriophage takes advantage of the bacterial DNA’s need for repair, while the bacteriophage itself has no need for this specific kind of repair. In this way the bacteriophage destroys the bacteria without suffering any damage to itself. The ability to distinguish between oneself and others is of enormous importance in nature and in various biological applications. Thus, for example, all antibiotic mechanisms identify and neutralize bacteria only, with minimal effect on human cells. Another example is our immune system, which is geared toward maximum damage to foreign factors, with minimal self-injury.”
The researchers discovered the process by searching for types of bacterial variants not impacted by this bacteriophage mechanism – those that have developed “immunity” to it. This inquiry led them to the specific bacterial mechanisms affected by the bacteriophage takeover. “We found that the ‘immune’ bacterial variants simply stopped repairing their DNA in ways that are vulnerable to the bacteriophage attack, thereby evading the bacteriophage’s destructive mechanism. Shedding more light on the ways in which bacteriophages attack bacteria, our findings may serve as a tool in the endless battle against antibiotic-resistant bacteria,” concludes Prof. Qimron.
Trilogy of papers provide insight into a critical step in how some viruses reproduce
A group of researchers have discovered the detailed inner workings of the molecular motor that packages genetic material into double-stranded DNA viruses. The advance provides insight into a critical step in the reproduction cycle of viruses such as pox- herpes- and adeno-viruses. It could also give inspiration to researchers creating microscopic machines based on naturally occurring biomotors.
The research was conducted by scientists from Duke University, the University of Minnesota, the University of Massachusetts and the University of Texas Medical Branch (UTMB). The results appear online in a trilogy of papers published in Science Advances, Proceedings of the National Academy of Sciences and Nucleic Acids Research.
“There were several missing pieces of information that prevented us from understanding how these kinds of DNA packaging motors work, which hindered our ability to design therapeutics or evolve new technologies,” said Gaurav Arya, professor of mechanical engineering and materials science, biomedical engineering, and chemistry at Duke. “But with new insights and simulations, we were able to piece together a model of this fantastic mechanism, which is the most detailed ever created for this kind of system.”
Viruses come in many varieties, but their classification generally depends upon whether they encode their genetic blueprints into RNA or single- or double-stranded DNA. The difference matters in many ways and affects how the genetic material is packaged into new viruses. While some viruses build a protein container called a capsid around newly produced RNA or DNA, others create the capsid first and then fill it with the genetic material.
“Trying to see the motor attached to the virus is like trying to see the details in the Statue of Liberty’s torch by taking a photo of the entire statue.”
— JOSHUA PAJAK.
Most double-stranded DNA viruses take the latter route, which presents many challenges. DNA is negatively charged and does not want to be crammed together into a small space. And it’s packaged into an extremely dense, nearly crystalline structure, which also requires a lot of force.
“The benefit of this is that, when the virus is ready to infect a new cell, the pressure helps inject DNA into the cell once it’s punctured,” said Joshua Pajak, a doctoral student working in Arya’s laboratory. “It’s been estimated that the pressure exceeds 800 PSI, which is almost ten times the pressure in a corked bottle of champagne.”
Forcing DNA into a tiny capsid at that amount of pressure requires an extremely powerful motor. Until recently, researchers only had a vague sense of how that motor worked because of how difficult it is to visualize. The motor only assembles on the virus particle, which is enormous compared to the motor.
“Trying to see the motor attached to the virus is like trying to see the details in the Statue of Liberty’s torch by taking a photo of the entire statue,” said Pajak.
But at a recent conference, Pajak learned that Marc Morais, professor of biochemistry and molecular biology at UTMB, and Paul Jardine, professor of diagnostic and biological sciences at the University of Minnesota, had been working on this motor for years and had the equipment and skills needed to see the details. Some of their initial results appeared to match the models Pajak was building with what little information was already available. The group grew excited that their separate findings were converging toward a common mechanism and quickly set about solving the mystery of the viral motor together.
In a paper published in Science Advances, Morais and his colleagues resolved the details of the entire motor in one of its configurations. They found that the motor is made up of five proteins attached to one another in a ring-like formation. Each of these proteins are like two suction cups with a spring in between, which allows the bottom portion to move vertically in a helical formation so that it can grab onto the helical backbone of DNA.
“Because you could fit about 100,000 of these motors on the head of a pin and they’re all jiggling around, getting a good look at them proved difficult,” said Morais. “But after my UTMB colleagues Michael Woodson and Mark White helps us image them with a cryo-electron microscope, a general framework of the mechanism fell into place.”
In a second paper, published in Nucleic Acids Research, the Morais group captured the motor in a second configuration using x-ray crystallography. This time the bottom suction cups of the motor were all scrunched up together in a planar ring, leading the researchers to imagine that the motor might move DNA into the virus by ratcheting between the two configurations.
“Joshua pieced together lots of clues and information to create this model. But a model is only useful if it can predict new insights that we didn’t already know.”
— GAURAV ARYA
To test this hypothesis, Pajak and Arya performed heavy-duty simulations on Anton 2, the fastest supercomputer currently available for running molecular dynamics simulations. Their results not only supported the proposed mechanism, but also provided information on how exactly the motor’s cogs contort between the two configurations.
While the tops of the proteins remain statically attached to the virus particle, their bottom halves move up and down in a cyclic pattern powered by an energy-carrying molecule called ATP. Once all the proteins have moved up—dragging the DNA along with them—the proteins release the byproduct of the ATP chemical reaction. This causes the lower ring to release the DNA and reach back down into their original helical state, where they once again grab on to more ATP and DNA to repeat the process.
“Joshua pieced together lots of clues and information to create this model,” said Arya. “But a model is only useful if it can predict new insights that we didn’t already know.”
At its core, the model is a series of mechanical actions that must fit together and take place in sequential order for everything to work properly. Pajak’s simulations predicted a specific series of mechanical signals that tell the bottoms of the proteins whether or not they should be gripping the DNA. Like a line of dominoes falling, removing one of the signaling pathways from the middle should stop the chain reaction and block the signal.
“All technology is inspired by nature in one way or another. Now that we really know how this molecular motor works, hopefully it will inspire other researchers to create new inventions using these same mechanisms.”
— GAURAV ARYA
To validate this prediction, the researchers turned to Jardine and colleagues Shelley Grimes and Dwight Anderson to see if removing one of the signaling dominoes actually stopped the motor from packaging DNA. A third paper, published in PNAS, shows that the sabotage worked. After mutating a domino in the signaling pathway so that it was unable to function, the motor could still bind and burn fuel just as well as ever, but it was much worse at actually packaging DNA.
“The new mechanism predicted by the high-resolution structures and the detailed predictions provided a level of detail greater than we ever previously had,” said Jardine. “This allowed us to test the role of critical components of the motor, and therefore assess the validity of this new mechanism as we currently understand it.”
The result is a strong indication that the model is very close to describing how the motor behaves in nature. The group plans to continue their highly integrated structural, biochemical and simulation approach to further test and refine the proposed model. They hope that that this fundamental understanding could potentially be used to someday fight disease or create a synthetic molecular motor.
“All technology is inspired by nature in one way or another,” said Arya. “Now that we really know how this molecular motor works, hopefully it will inspire other researchers to create new inventions using these same mechanisms.”
This work was supported by the National Institutes of Health (GM118817, GM122979, GM127365) and the National Science Foundation (MCB1817338). Cryo-EM data were also collected at NIH-supported regional cryo-EM imaging facilities (1U24 GM116787-01, 1U24 GM116792-01). Simulations were performed on Anton 2 supercomputer made available by D.E. Shaw Research and hosted at the Pittsburgh Supercomputing Center via the NIH (R01GM116961) and the Comet supercomputer hosted at the San Diego Supercomputer Center via the NSF (ACI-1053575).
“Viral Packaging ATPases Utilize a Glutamate Switch to Couple ATPase Activity and DNA Translocation.” Joshua Pajak, Rockney Atz, Brendan J. Hilbert, Marc C. Morais, Brian A. Kelch, Paul Jardine, and Gaurav Arya. PNAS, April 27, 2021 118 (17) e2024928118. DOI: 10.1073/pnas.2024928118
“A Viral Genome Packaging Motor Transitions Between Cyclic and Helical Symmetry to Translocate dsDNA,” Michael Woodson, Joshua Pajak, Bryon P. Mahler, Wei Zhao, Wei Zhang, Gaurav Arya, Mark A. White, Paul J. Jardine and Marc C. Morais. Science Advances, 07 May 2021: Vol. 7, no. 19, eabc1955. DOI: 10.1126/sciadv.abc1955
“Atomistic Basis Of Force Generation, Translocation, and Coordination in a Viral Genome Packaging Motor,” Joshua Pajak, Erik Dill2, Emilio Reyes-Aldrete, Mark A. White, Brian A.Kelch, Paul J. Jardine, Gaurav Arya1, and Marc C. Morais. Nucleic Acids Research, 2021. DOI: 10.1093/nar/gkab372
UC San Diego School of Medicine researchers identify how the body regulates and prevents constant skin inflammation
The human body is constantly exposed to various environmental actors, from viruses to bacteria to fungi, but most of these microbial organisms provoke little or no response from our skin, which is charged with monitoring and protecting from external dangers.
Until now, researchers weren’t quite sure how that happened — and why our skin wasn’t constantly alarmed and inflamed.
In a study published May 21, 2021 in Science Immunology, scientists at University of California San Diego School of Medicine identify and describe two enzymes responsible for protecting our skin and body’s overall health from countless potential microbial intruders. These enzymes, called histone deacetylases (HDACs), inhibit the body’s inflammatory response in the skin.
“We have figured out why we tolerate certain microbes living on our skin, while the same bacteria would make us very sick if exposed elsewhere in the body,” said Richard Gallo, MD, PhD, Ima Gigli Distinguished Professor of Dermatology and chair of the Department of Dermatology at UC San Diego School of Medicine. “In our research, we identified enzymes that act on the chromosome of specific skin cells that provide immune tolerance by the skin.
“Without these enzymes telling our cells to ignore certain bacteria, we’d have a constant rash on our skin.”
Gallo and colleagues say the potential mechanism for how the environment can interact and alter cell function is through epigenetic control of gene expression. Within the skin cells, proteins called toll-like receptors (TLRs) allow the cells to sense their surroundings and potential dangers.
In most organs, TLRs act as a warning system that triggers an inflammatory response to threats. But in skin cells, the two identified HDAC enzymes, HDAC8 and HDAC9, inhibit the inflammatory response.
“This is one of the first demonstrations of how the microbiome can interact with epigenetic factors in the skin and modulate the skin’s behavior through the inflammatory response,” said George Sen, PhD, associate professor of dermatology and cellular and molecular medicine at UC San Diego School of Medicine. “Whatever environment we’re facing can change a person’s specific response to it. Since this epigenetic change is reversible, unlike alterations to our DNA, we can potentially control our skin inflammatory response through targeting of these enzymes.”
The research was initially conducted in mouse models in which HDAC8 and HDAC9 had been genetically knocked out. As a result, the mice’s skin could not tolerate microbial or viral exposures, resulting in a heightened immune reaction. The team then reproduced the findings with human cells in a culture dish.
Gallo said the work could change how doctors treat certain types of skin inflammation or other dermatologic conditions.
“This is a completely new way to think about skin immune regulation,” said Gallo. “Through alterations in HDAC activity, we’ve provided a possible way to explore and quiet down unnecessary inflammation by working with skin cells themselves. In the future, drugs designed to turn these enzymes on or off could help treat skin disease as an alternative to antibiotics.”
Co-authors include: Yu Sawada, Teruaki Nakatsuji, Tatsuya Dokoshi, Nikhil Nitin Kulkarni and Marc C. Liggins, all at UC San Diego.
The research was funded, in part, by the National Institutes of Health (R01AR069653, R01AR074302, R01AR076082, R37AI052453, U01AI52038).
Reference: Yu Sawada, Teruaki Nakatsuji, Tatsuya Dokoshi et al., “Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9”, Science Immunology 21 May 2021: Vol. 6, Issue 59, eabe1935 DOI: https://doi.org/10.1126/sciimmunol.abe1935
Since our ancestors infected themselves with retroviruses millions of years ago, we have carried elements of these viruses in our genes – known as human endogenous retroviruses, or HERVs for short. These viral elements have lost their ability to replicate and infect during evolution, but are an integral part of our genetic makeup. In fact, humans possess five times more HERVs in non-coding parts than coding genes. So far, strong focus has been devoted to the correlation of HERVs and the onset or progression of diseases. This is why HERV expression has been studied in samples of pathological origin. Although important, these studies do not provide conclusions about whether HERVs are the cause or the consequence of such disease.
Today, new technologies enable scientists to receive a deeper insight into the mechanisms of HERVs and their function. Together with her colleagues, virologist Michelle Vincendeau* has now succeeded for the first time in demonstrating the negative effects of HERV activation on human brain development.
HERV activation impairs brain development
Using CRISPR technology, the researchers activated a specific group of human endogenous retroviruses** in human embryonic stem cells and generated nerve cells (neurons). These viral elements in turn activated specific genes, including classical developmental factors, involved in brain development. As a result, cortical neurons, meaning the nerve cells in our cerebral cortex, lost their function entirely. They developed very differently from healthy neurons in this brain region – with much a shorter axon (nerve cell extension) that were much less branched. Thus, activation of one specific HERV group impairs cortical neuron development and ultimately brain development.
Since neurodegenerative diseases are often associated with the activation of several HERV groups, the negative impact of HERV activation on cortical neuron development is an essential finding. It is already known that environmental factors such as viruses, bacteria, and UV light can activate distinct HERVs, thereby potentially contributing to disease onset. This knowledge, in turn, makes HERVs even more interesting for clinical application. Switching off distinct viral elements could open up a new field of research for the treatment of patients with neurodegenerative diseases. In a next step, the group at Helmholtz Zentrum München will study the impact of HERV deactivation in neurons in the context of disease.
New paths for basic research
In addition, the research findings provide important indications that epigenetic mechanisms keep viral elements under control in healthy brain development. Michelle Vincendeau even suspects a functional role for the controlled HERVs in normal brain development. “We have carried these elements for about 40 to 70 million years. We assume that their presence is relevant to our natural processes, otherwise we would not have retained them for so long during evolution,” Vincendeau says. Further basic research in this direction might reveal new functional roles for HERVs.
* Michelle Vincendeau leads the research group for Human Endogenous Retroviruses at the Institute of Viorology at Helmholtz Zentrum München. Part of the data from the current study was generated in the context of her previous work at the Memorial Sloan Kettering Cancer Center in New York. For this paper, she also collaborated with researchers at the Technical University of Munich and the University of Saarland.
Scientists investigate the evolution of Mimivirus, one of the world’s largest viruses, through how they replicate DNA
Researchers from the Indian Institute of Technology Bombay shed light on the origins of Mimivirus and other giant viruses, helping us better understand a group of unique biological forms that shaped life on earth. In their latest study published in Molecular Biology and Evolution, the researchers show that giant viruses may have come from a complex singlecell ancestor, keeping DNA replication machinery but shedding genes that code for other vital processes like metabolism.
2003 was a big year for virologists. The first giant virus was discovered in this year, which shook the virology scene, revising what was thought to be an established understanding of this elusive group and expanding the virus world from simple, small agents to forms that are as complex as some bacteria. Because of their link to disease and the difficulties in defining them—they are biological entities but do not fit comfortably in the existing tree of life— viruses incite the curiosity of many people.
Scientists have long been interested in how viruses evolved, especially when it comes to giant viruses that can produce new viruses with very little help from the host—in contrast to most small viruses, which utilize the host’s machinery to replicate.
Even though giant viruses are not what most people would think of when it comes to viruses, they are actually very common in oceans and other water bodies. They infect single-celled aquatic organisms and have major effects on the latter’s population. In fact, Dr. Kiran Kondabagil, molecular virologist at the Indian Institute of Technology (IIT) Bombay, suggests, “Because these single-celled organisms greatly influence the carbon turnover in the ocean, the viruses have an important role in our world’s ecology. So, it is just as important to study them and their evolution, as it is to study the disease-causing viruses.”
In a recent study, the findings of which have been published in Molecular Biology and Evolution, Dr. Kondabagil and co-researcher Dr. Supriya Patil performed a series of analyses on major genes and proteins involved in the DNA replication machinery of Mimivirus, the first group of giant viruses to be identified. They aimed to determine which of two major suggestions regarding Mimivirus evolution—the reduction and the virus-first hypotheses— were more supported by their results. The reduction hypothesis suggests that the giant viruses emerged from unicellular organisms and shed genes over time; the virus-first hypothesis suggests that they were around before single-celled organisms and gained genes, instead.
Dr. Kondabagil and Dr. Patil created phylogenetic trees with replication proteins and found that those from Mimivirus were more closely related to eukaryotes than to bacteria or small viruses. Additionally, they used a technique called multidimensional scaling to determine how similar the Mimiviral proteins are. A greater similarity would indicate that the proteins coevolved, which means that they are linked together in a larger protein complex with coordinated function. And indeed, their findings showed greater similarity. Finally, the researchers showed that genes related to DNA replication are similar to and fall under purifying selection, which is natural selection that removes harmful gene variants, constraining the genes and preventing their sequences from varying. Such a phenomenon typically occurs when the genes are involved in essential functions (like DNA replication) in an organism.
Taken together, these results imply that Mimiviral DNA replication machinery is ancient and evolved over a long period of time. This narrows us down to the reduction hypothesis, which suggests that the DNA replication machinery already existed in a unicellular ancestor, and the giant viruses were formed after getting rid of other structures in the ancestor, leaving only replication-related parts of the genome.
“Our findings are very exciting because they inform how life on earth has evolved,” Dr. Kondabagil says. “Because these giant viruses probably predate the diversification of the unicellular ancestor into bacteria, archaea, and eukaryotes, they should have had major influence on the subsequent evolutionary trajectory of eukaryotes, which are their hosts.” In terms of applications beyond this contribution to basic scientific knowledge, Dr. Kondabagil feels that their work could lay the groundwork for translational research into technology like genetic engineering and nanotechnology. He says, “An increased understanding of the mechanisms by which viruses copy themselves and self-assemble means we could potentially modify these viruses to replicate genes we want or create nanobots based on how the viruses function. The possibilities are far-reaching!”
URL to published work
Patil S, Kondabagil K. Coevolutionary and Phylogenetic Analysis of Mimiviral Replication Machinery Suggest the Cellular Origin of Mimiviruses. Mol Biol Evol. 2021 May 4;38(5):2014-2029. doi: 10.1093/molbev/msab003. PMID: 33570580; PMCID: PMC8097291. https://pubmed.ncbi.nlm.nih.gov/33570580/