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A new look inside Ebola’s “viral factories”

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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

Additional authors of the study, “Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories,” include Guillaume Castillon, Sebastien Phan, Sara McArdle, Chitra Hariharan, and Aiyana Adams.

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.

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DOI: 10.1038/s41467-023-39821-7

Source: La Jolla Institute for Immunology

About La Jolla Institute

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.

Journal Link: Nature Communication, July-2023

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Connected Communities: Reducing the Impact of Isolation in Rural Areas

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isolation (Family Features) Throughout history, humans’ ability to rely on one another has been crucial to survival. Despite modern developments that help individuals live with minimal human engagement, the human need to connect remains. However, in many parts of America, a trend toward isolation is emerging. Over the past two decades, people are spending more time alone and less time engaging with others in person, according to data from the Office of the U.S. Surgeon General. One segment of Americans at particular risk of social isolation, loneliness and their negative impacts are select populations who live in rural areas. “There is an urgent need to take action and improve mental health in rural America,” said Jeff Winton, dairy farmer and founder and chairman of Rural Minds, a nonprofit mental health advocacy organization that partnered with Pfizer to raise awareness about the physical and mental risks of social isolation. “Challenges to mental health can be inherent in a rural lifestyle, including a belief in self-reliance as a virtue, fear of judgment and difficulty getting an appointment with a limited number of mental health professionals, among others.” Many Americans are increasingly spending more time alone according to the American Time Use Survey. They are increasingly more likely to take meetings, shop, eat and enjoy entertainment at home, making it easier for them to stay within their own four walls and avoid social interactions. Authentic human connection is a basic but often unacknowledged necessity for health, “as essential to survival as food, water and shelter,” according to the U.S. Surgeon General’s Advisory on the Health Effects of Social Connection and Community. Understanding Social Isolation According to the Centers for Disease Control and Prevention (CDC), about one-third of U.S. adults reported feeling lonely and about one-fourth said they don’t have social and emotional support (the basis of social isolation). The concepts of social isolation and loneliness can go hand-in-hand, but the two are actually quite different. Social isolation is defined by an absence of relationships or contact with others. Someone experiencing loneliness may or may not have social connections, but lacks feelings of closeness, support or belonging. Despite the distinction, both can have a negative impact on a person’s mental and even physical health. Several factors can influence a person’s risk for social isolation and loneliness. “Social connection is a dynamic that changes over time,” said Nikki Shaffer, senior director, occupational health and wellness, Pfizer. “Transient feelings of loneliness or solitude may be beneficial because they can serve as motivation to reconnect. However, chronic loneliness (even if someone is not isolated) and isolation (even if someone is not lonely) can represent significant health concerns.” 17384 detail image embed1 Isolation in Rural America Compared to people who live in urban areas, many rural Americans experience higher rates of depression and suicide but are less likely to access mental health care services, according to the “Health Disparities in Rural America: Current Challenges and Future Solutions” study published in “Clinical Advisor.” What’s more, CDC data shows suicide rates among people living in rural areas can be 64-68% higher than those in large urban areas. Rural areas have 20% fewer primary care providers compared to urban areas, according to a report in JAMA, and the Health Resources and Services Administration reports more than 25 million rural Americans, more than half of rural residents, live in mental health professional shortage areas. Among rural counties, 65% lack a psychiatrist. Nearly 30% of rural Americans don’t have internet access in their homes, which complicates the option for telehealth. These figures from Rural Minds exemplify the challenges facing rural America. “Some people in rural communities still don’t understand or accept that mental illness is a disease,” said Winton, who grew up on a rural farm. “Rather, a mental illness can often be viewed as a personal weakness or character flaw. A lot of the stigma around mental illness results in unwarranted shame, which adds to the burden for someone already suffering from mental illness.” Health Impacts of Social Isolation Loneliness is far more than just a bad feeling; it harms both individual and societal health. In fact, loneliness and social isolation can increase the risk for premature death by 26% and 29%, respectively. Lacking social connection can increase the risk for premature death as much as smoking up to 15 cigarettes a day or drinking six alcoholic drinks daily. In addition, poor or insufficient social connection is associated with increased risk of disease, including a 29% increased risk of heart disease and a 32% increased risk of stroke. Social isolation is also associated with increased risk for anxiety, depression and dementia. Additionally, a lack of social connection may increase susceptibility to viruses and respiratory illness. Learn more about the impact of social isolation, especially on residents of rural areas, and the steps you can take to reduce isolation and loneliness by visiting ruralminds.org.

Boost Your Social Connections

Take a proactive approach to combatting social isolation and loneliness with these everyday actions that can promote stronger social ties.
  • Invest time in nurturing your relationships through consistent, frequent and high-quality engagement with others. Take time each day to reach out to a friend or family member.
  • Minimize distractions during conversation to increase the quality of the time you spend with others. For instance, don’t check your phone during meals with friends, important conversations and family time.
  • Seek out opportunities to serve and support others, either by helping your family, co-workers, friends or people in your community or by participating in community service.
  • Be responsive, supportive and practice gratitude. As you practice these behaviors, others are more likely to reciprocate, strengthening social bonds, improving relationship satisfaction and building social capital.
  • Participate in social and community groups such as religious, hobby, fitness, professional and community service organizations to help foster a sense of belonging, meaning and purpose.
  • Seek help during times of struggle with loneliness or isolation by reaching out to a family member, friend, counselor, health care provider or the 988 crisis line.
  Photos courtesy of Shutterstock   collect?v=1&tid=UA 482330 7&cid=1955551e 1975 5e52 0cdb 8516071094cd&sc=start&t=pageview&dl=http%3A%2F%2Ftrack.familyfeatures SOURCE: Rural Minds and Pfizer

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Living with a Bleeding Disorder

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(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:

  • Receive follow-up care
  • Monitor your condition
  • Adopt healthy lifestyle changes

To learn more about bleeding disorders, visit nhlbi.nih.gov/health/bleeding-disorders.

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.

“It doesn’t have to be a limitation,” White said.

Photo courtesy of Shutterstock

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SOURCE:
National Heart, Lung, and Blood Institute

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5 Things Funeral Directors Wish Everyone Knew

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Funeral directors (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.
  1. 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.

  1. 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.

  1. 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.

  1. 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.

  1. 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 collect?v=1&tid=UA 482330 7&cid=1955551e 1975 5e52 0cdb 8516071094cd&sc=start&t=pageview&dl=http%3A%2F%2Ftrack.familyfeatures SOURCE: National Funeral Directors Association


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