Credit: Image courtesy Saphire Lab, La Jolla Institute for Immunology Two views of Ebola’s “viral factories” inside host cells. The image on the left was captured via confocal immunofluorescence microscopy and shows Ebola’s viral factories in pink. The image on the right was captured using electron tomography and shows viral factories in orange.
Newswise — LA JOLLA, CA—New research in the journal Nature Communications gives scientists an important window into how Ebola virus replicates inside host cells. The study, led by scientists at La Jolla Institute for Immunology (LJI), reveals the inner workings of “viral factories,” clusters of viral proteins and genomes that form in host cells.
The research team, which included experts from Scripps Research and UC San Diego School of Medicine, found that Ebola virus’s replication machinery forms fascinating microscopic structures that become viral factories. By understanding the architecture and function of these microscopic manufacturing hubs, researchers may be closer to developing new therapies that interrupt the Ebola virus life cycle and prevent severe disease.
“We are imaging these fluid and dynamic assembly centers for the first time. Understanding how they work and what they require gives us the information needed to defeat them,” says LJI President and CEO Erica Ollmann Saphire, Ph.D., senior author of the new study.
What is a viral factory?
Scientists first spotted what would turn out to be “virus factories” in virus-infected animal cells back in the 1960s, but they didn’t know what they were seeing. Within a sea of normal cellular proteins, these areas looked like fuzzy splotches.
“People had already seen that Ebola-infected cells had these ‘inclusions,’” says LJI Postdoctoral Researcher Jingru Fang, Ph.D., first author of the new study. For a long time, scientists thought of these “inclusions” as helpful visual indicators of infection, without understanding their true purpose. “But in fact, these ‘inclusion bodies’ actively gather an enormous quantity of viral proteins and viral RNAs.”
Many viral pathogens, including rabies virus and RSV (respiratory syncytial virus) form inclusions in host cells, Fang explains. “Recent studies suggest that these cellular inclusions are the site where viruses make their RNA genomes. They are ‘viral factories’ with actual functional purpose: to offer a secured space for viral RNA synthesis,” says Fang. “The process of viral RNA synthesis involves flux of viral building blocks. This means molecules gathered inside viral factories should be able to move freely rather than being static.”
For the new study, Saphire, Fang and their colleagues wondered: Can we observe the movement of viral building blocks directly in living cells?
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Fang began by tagging a viral protein called VP35 with a fluorescent marker that makes the protein glow in the dark. VP35 is a critical component of the viral factory and is important for viral RNA synthesis (and the making of new copies of Ebola virus). Working with imaging experts in the LJI Microscopy and Histology Core, Fang followed the glowing proteins in live cells, which express a simplified and non-infectious version of Ebola viral factories.
Under the microscope, Fang and colleagues could indeed see and even measure how molecules move inside the viral factories formed in host cells. This finding added evidence that viral proteins are clumping together like droplets so they can churn out the proteins needed to help the virus replicate. Those mysterious inclusions really are viral factories. The researcher dubbed these “droplet-like” viral factories.
Then the scientists saw something odd. Some of the glowing proteins didn’t gather into clumps. Instead, they joined up with a smattering of other viral proteins, creating a fluorescent swirl that evoked van Gogh’s “Starry Night.” These trails of viral proteins still had the right ingredients to replicate Ebola virus, so the scientists dubbed them “network-like” viral factories.
“These are two different flavors of the viral factory,” says Fang. “People have mostly focused on the droplet-like form, which is the majority, and not paid too much attention to this other form.”
Besides their shapes, there was a key difference between the two factories. It appeared the network-like factories had the right ingredients for the incoming Ebola virus to express its genes, but they didn’t actually produce virus progenies.
A multi-tasking machine
Next, the researchers looked at a key player in infection: a protein called virus polymerase. Polymerase is a multifunctional nanomachine that comes with the virus. This machine not only copies the Ebola virus genomic material, it also transcribes the viral genome into messenger RNAs, which instruct infected cells to produce loads of viral proteins. The researchers wanted to understand how this viral machine functions inside viral factories.
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Ebola virus polymerase is already known as a hard-working protein—all Ebola viral proteins have to be. Ebola virus is a highly efficient pathogen because it gets by with just seven genes (humans have more than 20,000 genes). Saphire has led research showing that Ebola virus survives by making proteins that can transform and take on different jobs during the course of infection.
Just last year, Saphire, Fang, and collaborators published a related discovery that viral polymerase actually harnesses a druggable human protein to help the virus replicate its genome. The team reported that while polymerase is essential for viral replication, the polymerase doesn’t actually jump into action until infection is well underway.
This work was important for understanding how polymerase stepped into action, but scientists also needed to know where polymerase was active. Fang knew it would be important to look at what polymerase might be up to in viral factories.
The researchers discovered that polymerase actually builds its own special structures inside viral factories. Many copies of polymerase gather in small bundles, called foci. The researchers found that these bundles spread out when a droplet-like viral factory starts replicating viral material.
Scientists aren’t sure exactly why polymerase needs to form bundles before it can do its job, but the spatial arrangement of the bundles must be important. As Fang points out, the idea of many small components coming together to build a structure isn’t a new concept in nature. “You can use a beehive or coral reef as the analogy to help understand why a specific spatial arrangement is important for a biological system to function,” she says.
With this finding, scientists now know how to find different kinds of viral factories and how polymerase organizes itself down on the factory floor.
Fighting back
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More than 30 human pathogens are known to assemble viral factories inside host cells, including respiratory syncytial virus (RSV) and even rabies virus. With this new view of Ebola’s viral factories, the scientists are curious whether other viruses construct similar forms of viral factories—and whether other viruses use their own versions of polymerase in the same way.
“If that’s true, maybe we can target the feature of viral factory formation that has been shared by multiple different viruses,” says Fang.
Going forward, Fang would also like to study how Ebola virus forms viral factories in different kinds of host cells. Do these viral factories look different in cells from animals (such as the virus’s natural hosts, the fruit bats) that can carry the virus around without getting sick? “Can we find some explanation for host-specific viral pathogenesis?” she asks.
The new study also demonstrates the importance of collaboration across San Diego’s Torrey Pines Mesa. The LJI team worked closely with Scripps Research Professor Ashok Deniz, Ph.D., and UC San Diego Professor Mark H. Ellisman, Ph.D., Director of the National Center for Microscopy and Imaging Research.
“The combination of state-of-the-art tools available on the Torrey Pines Mesa allowed us to combine the biophysical characterization with the human health insight,” says Saphire
This study was supported by the National Institute of Health (grants NIH S10OD021831, R24GM137200, and S10OD021784), an Imaging Scientist grant (2019‐198153) from the Chan Zuckerberg Initiative, LJI institutional funds, and the Donald E. and Delia B. Baxter Foundation Fellowship.
The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. Visit lji.org for more information.
(Family Features) Many people don’t think much about whether their blood is clotting properly. However, when you have a bleeding disorder, a condition that affects the way your body controls clots, it’s no small matter.
According to the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, abnormal clotting can lead to a host of problems, including excessive bleeding after an injury or during surgery.
About 3 million people in the U.S. have bleeding disorders. Some types, such as hemophilia, are inherited, meaning a person who has it is born with it. Inherited bleeding disorders are caused by certain genes passed down from parents to children. These genes contain instructions for how to make proteins in the blood called clotting factors, which help blood clot. If there is a problem with one of these genes, such as a mutation – a change in the gene’s instructions – the body may make a clotting factor incorrectly or not make it at all.
You can also have what’s called an acquired bleeding disorder, meaning you develop it during your lifetime. Acquired bleeding disorders can be caused by medical conditions, medicines or something unknown. Your risk of developing a bleeding disorder depends on your age, family history, genes, sex, or other medical conditions. If bleeding disorders run in your family, you may have a higher risk of developing or inheriting one.
Symptoms of a bleeding disorder may appear soon after birth or develop later in life and can include:
Excessive bleeding or bruising, such as frequent or long nose bleeds (longer than 15 minutes) or frequent or long menstrual periods
Petechiae, which are tiny purple, red, or brown spots caused by bleeding under the skin
Redness, swelling, stiffness, or pain from bleeding into muscles or joints
Blood in urine or stool
Excessive umbilical stump bleeding
Excessive bleeding during surgery or after trauma
If you believe you, or someone you care for, may have a bleeding disorder, talk to a health care provider. Your provider may make a diagnosis based on symptoms, risk factors, family history, a physical exam, and diagnostic tests. Health care providers typically screen for bleeding disorders only if you have known risk factors or before certain surgeries.
How your bleeding disorder is treated depends on its type. If your disorder causes few or no symptoms, you may not need treatment. If you have symptoms, you may need daily treatment to prevent bleeding episodes, or you may need it only on certain occasions, such as when you have an accident or before a planned surgery.
If you have been diagnosed with a bleeding disorder, it’s important to be proactive about your health and follow your treatment plan. To lower your risk of complications:
A Story of Bravery, Balance, and a Bleeding Disorder
There are lots of things that make Mikey White Jr. special. He’s a dedicated athlete. He’s determined, disciplined, and optimistic. He’s also living with hemophilia, a type of bleeding disorder.
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White was diagnosed with hemophilia at age 3 after experiencing several severe bleeding episodes. He had to give up baseball and basketball, his passions, because of the high risk of injuries, but he found competitive swimming – and he’s been breaking records ever since.
“Competitive swimming is a noncontact sport, so it complements my hemophilia while still being an intense and rigorous sport,” White said.
Being an athlete with hemophilia requires support, White admits. He works with his healthcare team and coaching staff to make sure he safely manages his condition and balances it with his training. He hopes his story encourages others living with bleeding disorders to accept and appreciate their bodies the way they are.
(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
It’s Never Too Early to Start Planning
While everyone knows death and taxes are inevitable, conversations about death are often avoided.
Simply documenting your wishes and discussing your preferences with your family can alleviate the difficult decisions your loved ones will have to make in the future. Speak with a funeral director to explore the many options for planning a meaningful funeral.
Legal and Financial Details Can Cause Unexpected Issues
Families often don’t realize power of attorney ends at death, meaning a designated person can no longer make decisions or access bank accounts once an individual dies.
To avoid complications, consider adding a trusted loved one to your bank account and ensure life insurance beneficiaries are up to date. Too often, deceased individuals leave minor children, deceased spouses or former partners as beneficiaries, leading to legal and financial challenges.
Final Wishes Shouldn’t Be In Your Will
Many people believe the best place to document their final wishes is in their will. However, wills are often not read until after funeral services take place, making them an unreliable way to communicate last requests. Instead, discuss and document your wishes with family members or a trusted funeral professional who can keep your wishes on file until there is a need.
There Are a Variety of Memorialization Options
End-of-life planning offers more choices than many realize. While burial remains a common preference, cremation is an increasingly popular choice and can even include a viewing and funeral service. Additionally, eco-friendly options, such as alkaline hydrolysis, natural burial and natural organic reduction are becoming more widely available for those seeking green memorialization. In fact, according to NFDA’s 2024 Consumer Awareness and Preferences Study, 68% of respondents expressed interest in green funeral options.
Exploring these possibilities with a funeral professional can help ensure your final arrangements reflect your values, traditions and personal wishes.
Funeral Directors Don’t Just Manage Funerals – They’re Trusted Guides In Honoring Life
Funeral directors play a vital role in helping families create meaningful services that reflect their loved one’s life, values and traditions. Whether planning ahead or facing a recent loss, funeral professionals provide expertise, compassionate care and personalized guidance during one of life’s most difficult moments.
Choosing the right funeral director is an important decision and finding someone who understands your needs can make all the difference in honoring your loved one in a personal and meaningful way.
Start the conversation today by talking about end-of-life planning. It isn’t easy, but it’s one of the most important conversations you can have with your loved ones. A little planning today can make a world of difference tomorrow.
Use comprehensive resources like RememberingALife.com, which is designed to guide families through every stage of the journey, including planning, funeral options and grief resources. The site offers valuable tools and support, such as the “Find a Funeral Home” tool to connect families with compassionate, local funeral directors and much more.
Photo courtesy of Shutterstock
SOURCE:National Funeral Directors Association
Workers who are in frequent contact with potentially sick animals are at high risk of bird flu infection.
Costfoto/NurPhoto via Getty ImagesRon Barrett, Macalester College
Disease forecasts are like weather forecasts: We cannot predict the finer details of a particular outbreak or a particular storm, but we can often identify when these threats are emerging and prepare accordingly.
The viruses that cause avian influenza are potential threats to global health. Recent animal outbreaks from a subtype called H5N1 have been especially troubling to scientists. Although human infections from H5N1 have been relatively rare, there have been a little more than 900 known cases globally since 2003 – nearly 50% of these cases have been fatal – a mortality rate about 20 times higher than that of the 1918 flu pandemic. If the worst of these rare infections ever became common among people, the results could be devastating.
Approaching potential disease threats from an anthropological perspective, my colleagues and I recently published a book called “Emerging Infections: Three Epidemiological Transitions from Prehistory to the Present” to examine the ways human behaviors have shaped the evolution of infectious diseases, beginning with their first major emergence in the Neolithic period and continuing for 10,000 years to the present day.
Viewed from this deep time perspective, it becomes evident that H5N1 is displaying a common pattern of stepwise invasion from animal to human populations. Like many emerging viruses, H5N1 is making incremental evolutionary changes that could allow it to transmit between people. The periods between these evolutionary steps present opportunities to slow this process and possibly avert a global disaster.
Spillover and viral chatter
When a disease-causing pathogen such as a flu virus is already adapted to infect a particular animal species, it may eventually evolve the ability to infect a new species, such as humans, through a process called spillover.
Spillover is a tricky enterprise. To be successful, the pathogen must have the right set of molecular “keys” compatible with the host’s molecular “locks” so it can break in and out of host cells and hijack their replication machinery. Because these locks often vary between species, the pathogen may have to try many different keys before it can infect an entirely new host species. For instance, the keys a virus successfully uses to infect chickens and ducks may not work on cattle and humans. And because new keys can be made only through random mutation, the odds of obtaining all the right ones are very slim.
Given these evolutionary challenges, it is not surprising that pathogens often get stuck partway into the spillover process. A new variant of the pathogen might be transmissible from an animal only to a person who is either more susceptible due to preexisting illness or more likely to be infected because of extended exposure to the pathogen.
Even then, the pathogen might not be able to break out of its human host and transmit to another person. This is the current situation with H5N1. For the past year, there have been many animal outbreaks in a variety of wild and domestic animals, especially among birds and cattle. But there have also been a small number of human cases, most of which have occurred among poultry and dairy workers who worked closely with large numbers of infected animals.
Pathogen transmission can be modeled in three stages. In Stage 1, the pathogen can be transmitted only between nonhuman animals. In stage 2, the pathogen can also be transmitted to humans, but it is not yet adapted for human-to-human transmission. In Stage 3, the pathogen is fully capable of human-to-human transmission.Ron Barrett, CC BY-SA
Epidemiologists call this situation viral chatter: when human infections occur only in small, sporadic outbreaks that appear like the chattering signals of coded radio communications – tiny bursts of unclear information that may add up to a very ominous message. In the case of viral chatter, the message would be a human pandemic.
Sporadic, individual cases of H5N1 among people suggest that human-to-human transmission may likely occur at some point. But even so, no one knows how long or how many steps it would take for this to happen.
Influenza viruses evolve rapidly. This is partly because two or more flu varieties can infect the same host simultaneously, allowing them to reshuffle their genetic material with one another to produce entirely new varieties.
Genetic reshuffling – aka antigenic shift – between a highly pathogenic strain of avian influenza and a strain of human influenza could create a new strain that’s even more infectious among people.Eunsun Yoo/Biomolecules & Therapeutics, CC BY-NC
These reshuffling events are more likely to occur when there is a diverse range of host species. So it is particularly concerning that H5N1 is known to have infected at least 450 different animal species. It may not be long before the viral chatter gives way to larger human epidemics.
Reshaping the trajectory
The good news is that people can take basic measures to slow down the evolution of H5N1 and potentially reduce the lethality of avian influenza should it ever become a common human infection. But governments and businesses will need to act.
People can start by taking better care of food animals. The total weight of the world’s poultry is greater than all wild bird species combined. So it is not surprising that the geography of most H5N1 outbreaks track more closely with large-scale housing and international transfers of live poultry than with the nesting and migration patterns of wild aquatic birds. Reducing these agricultural practices could help curb the evolution and spread of H5N1.
Large-scale commercial transport of domesticated animals is associated with the evolution and spread of new influenza varieties.ben/Flickr, CC BY-SA
People can also take better care of themselves. At the individual level, most people can vaccinate against the common, seasonal influenza viruses that circulate every year. At first glance this practice may not seem connected to the emergence of avian influenza. But in addition to preventing seasonal illness, vaccination against common human varieties of the virus will reduce the odds of it mixing with avian varieties and giving them the traits they need for human-to-human transmission.
At the population level, societies can work together to improve nutrition and sanitation in the world’s poorest populations. History has shown that better nutrition increases overall resistance to new infections, and better sanitation reduces how much and how often people are exposed to new pathogens. And in today’s interconnected world, the disease problems of any society will eventually spread to every society.
For more than 10,000 years, human behaviors have shaped the evolutionary trajectories of infectious diseases. Knowing this, people can reshape these trajectories for the better.Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
