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A new look inside Ebola’s “viral factories”



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?

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.

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

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.

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


Study finds risk factors for severe COVID-19 cases in children



UT Southwestern researchers show living in the Southern U.S., having preexisting conditions linked to more serious illness

Newswise — DALLAS – Nov. 21, 2023 – Children who had preexisting health problems or who lived in the Southern United States had a higher risk for severe health outcomes from acute COVID-19 infections, according to researchers at UT Southwestern Medical Center. The results, reported in the journal Hospital Pediatrics that is published by the American Academy of Pediatrics, also showed the importance of vaccinations in reducing the severity of illness for those who became infected.

“While receiving the COVID-19 vaccines did not mean that our little patients would not get sick from the virus, vaccines did protect them from more severe outcomes such as death and intensive care admissions. Protecting your children by immunizing them is a good thing, especially if your child has a preexisting condition, such as heart disease or asthma,” said one of the study’s authors, Christoph Lehmann, M.D., Professor of Pediatrics and in the Lyda Hill Department of Bioinformatics, Director of the Clinical Informatics Center, and a member of the Peter O’Donnell Jr. School of Public Health at UT Southwestern.

The national study analyzed records from 165,437 children age 18 and younger who tested positive for COVID-19 between January 2020 and January 2022. About 1.8% were hospitalized without complication, 1.8% were admitted to intensive care or needed intensive respiratory support, and 31 children died.

The researchers found that children in the Southern United States were more than three times as likely to have more severe complications compared with other areas of the country.

“It matters where you live,” Dr. Lehmann noted. “While we do not know what causes children in the South to have worse outcomes, our findings call for an exploration of possible causes – such as weather and climate, immunization rates, public health or government messaging, mandates, and closures.”

The study also found that among children under age 5, those younger than 2 years old were at the highest risk for severe outcomes. This finding contradicts initial anecdotal observations suggesting that infants were not as prone to severe disease with COVID-19 as they were from other respiratory viruses such as respiratory syncytial virus (RSV).

“While this wasn’t surprising to us – smaller airways are disproportionately affected by respiratory illness – it does mean that we have to be more vigilant when the little ones acquire COVID-19,” Dr. Lehmann added.

Finally, the study found that those with multiple chronic medical conditions, such as heart disease and lung disease, were more than twice as likely to have severe complications following COVID-19 infection, and the more chronic conditions they had, the higher the risk.

Other UTSW researchers who contributed to this study include lead author Robert W. Turer, M.D., Assistant Professor of Emergency Medicine; first author and medical student Milan Ho, B.S.; Trish M. Perl, M.D., M.Sc., Professor of Internal Medicine; Zachary M. Most, M.D., M.Sc., Assistant Professor of Pediatrics; Bhaskar Thakur, Ph.D., Assistant Professor of Family and Community Medicine, Emergency Medicine, and Physical Medicine & Rehabilitation and a member of the O’Donnell School of Public Health; John J. Hanna, M.D., Assistant Instructor of Internal Medicine; Marlon I. Diaz, B.S., Sameh Saleh, M.D., Madison Pickering, M.S., and Richard J. Medford, M.D., all with the Clinical Informatics Center; medical student Julia A. Casazza, B.S.; and Postdoctoral Research Fellow Alexander P. Radunsky, Ph.D.

Dr. Lehmann holds the Willis C. Maddrey, M.D. Distinguished Professorship in Clinical Science. Dr. Perl, a member of the O’Donnell School of Public Health, holds the H. Ben and Isabelle T. Decherd Chair in Internal Medicine in Honor of Henry M. Winans, Sr., M.D.

This study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1 TR003163).

Related research

Public Perception of COVID-19 Vaccines Through Analysis of Twitter Content and Users

Association of Healthcare Access With Intensive Care Unit Utilization and Mortality in Patients of Hispanic Ethnicity Hospitalized With COVID-19

Early Crowdfunding Response to the COVID-19 Pandemic: Cross-Sectional Study

What the Coronavirus Disease 2019 (COVID-19) Pandemic Has Reinforced: The Need for Accurate Data

Evaluating Short-Term Forecasting of COVID-19 Cases Among Different Epidemiological Models Under a Bayesian Framework

An “Infodemic”: Leveraging High-Volume Twitter Data to Understand Early Public Sentiment for the Coronavirus Disease 2019 Outbreak

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 26 members of the National Academy of Sciences, 20 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Journal Link: Hospital Pediatrics

Source: UT Southwestern Medical Center

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Family Caregivers are Filling the Gap



More than 53 million Americans serve as “informal” caregivers filling critical roles that make independent living possible for people with disabilities.

MIDDLEVILLE, MICHIGAN, UNITED STATES /EINPresswire.com/ — In the wake of a direct care worker shortage, more than 53 million Americans serve as “informal” caregivers filling critical roles that make independent living possible for people with disabilities and chronic health conditions. However, family caregiving can take a financial, emotional, and physical toll on those performing the unpaid work. Below, we explore five opportunities to help family caregivers build sustainable and strong caregiving relationships.

Family caregivers are critical resources in the quest to promote independence and autonomy among people with disabilities, and they deserve all the support our communities can offer.”

— Steve Locke

Determine Whether Payment is Possible

In some cases, family caregivers can receive financial compensation for their caregiving. Medicaid’s Self-Directed Services program, the Department of Veterans’ Affairs Veteran-Directed Care program, certain Home and Community-Based Services programs, many long-term care insurance plans, and even some employers offer stipends to informal caregivers providing necessary care.

Make a Plan for Respite Care
Creating a respite care plan helps caregivers build in time on a regular basis to take a break from caregiving and pass their responsibilities on to a trustworthy provider. The AARP outlines the process for creating a plan, including identifying what you and your loved one need and who could provide support. Professional respite care resources are available through the Senior Corps, local Area Agency on Aging, and Elder Helpers.

Find Peer Support
Up to 40% of informal caregivers report that caregiving makes them feel alone, yet there are many others experiencing the same scenarios and connecting can help caregivers cope. Your local Center for Independent Living can connect you with caregiving support groups, the Area Agency on Aging can provide assistance, or even nonprofit or religious groups like Courage to Caregivers that link volunteer peer mentors with caregivers.

Ask for Help!
The digital age has brought a wealth of apps that make it easier for caregivers to communicate their needs and get other friends and family members on board to help. Whether you need alternative transportation to a medical appointment or would love a friend to drop off dinner a few days per month, apps like Carely, Caring Village, and LotsaHands provide tools to help caregivers coordinate caregiving responsibilities among family and friends.

Pay Attention to your Mental Health
Up to 4 in 10 caregivers report that they “never relax,” and one survey revealed that more than half of caregivers polled had experienced suicidal ideation during the COVID pandemic. Caregiving while experiencing this level of mental anguish is dangerous for both the caregiver and the patient. In cases like this, finding an alternate source of care at least part of the time is necessary. Individuals in crisis can call 988 for 24/7 mental health support and the Caregiver Action Network can provide a listening ear, resources, and assistance.

Family caregivers are critical resources in the quest to promote independence and autonomy among people with disabilities, and they deserve all the support our communities can offer. As organizations like MiSILC advocate for formal and informal caregivers at the highest levels, nonprofits and community resources can provide the services necessary for effective, sustainable caregiving. Learn more about our work at MiSILC.org.
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Stay Balanced this Holiday Season with Health-Ade Kombucha



Celebrate the return of a seasonal favorite plus a new limited-edition collab

LOS ANGELES /PRNewswire/ — Health-Ade, makers of delicious, bubbly beverages that support a happy and healthy gut, are celebrating feeling good from the inside out this holiday season. A perfect swap for alcohol or soda, Health-Ade Kombucha’s living probiotics help keep your gut in balance while enjoying the season’s festivities and indulging in your favorite holiday foods. 

To celebrate the season, Health-Ade Kombucha has launched its seasonal holiday flavor, Holiday Cheers, which expertly blends notes of ginger, vanilla, allspice, and cacao for the perfect sip to spread the cheer all season long. This winter staple is a perfect accompaniment for sipping by the fire, enjoying as a festive treat, or even as a delicious probiotic hostess gift for those holiday parties and celebrations. Every bottle of Health-Ade’s Holiday Cheers Kombucha will help you celebrate the seasonal flavors you love, while supporting a happy and healthy gut.

“Health-Ade is a delicious, easy way to support your gut health during the holiday season,” says Claire Chewning, Health-Ade’s Registered Dietitian Advisor. “Good nutrition is all about adding IN, not restricting unnecessarily. Adding in sources of fermented foods and probiotics, like kombucha, can increase the number of good bacteria in your gut. For many, this can help manage symptoms of bloating and other digestive discomforts. For another gut-happy practice, you can also consider swapping alcohol for a few fun Health-Ade Kombucha mocktails. Cheers to a delicious and nourished holiday season!”

Special for this season, Health-Ade has partnered with fellow Los Angeles-based brand Mar Mar to create a limited edition Holiday Minis candle set. The Mar Mar x Health-Ade Kombucha collaboration features three best-selling Mar Mar scents reimagined with a Health-Ade twist. Titled The Bold, The Rebel, and The Optimist these 2oz votives are wrapped in Health-Ade’s beloved and recognizable color schemes to make the perfect gift set for anyone on your list and a great companion to your Health-Ade Kombucha selection.

You can purchase the limited-edition candle set and Holiday Cheers flavor now on health-ade.com for yourself and all of the Health-Ade Kombucha lovers on your holiday gift list. The Mini Candle set retails for $60, or you can bundle with your favorite case of Health-Ade for a $10 discount. Holiday Cheers can also be found at select retailers nationwide, while supplies last.

About Health-Ade Kombucha
Health-Ade creates feel-good, bubbly beverages with gut health benefits so you can follow your gut and show the world what you’re made of. The brand got started in the Brentwood Farmers Market in 2012 selling its flagship kombucha drinks. Instantly gaining a cult following in Southern California, Health-Ade Kombucha rapidly expanded to sell nationwide in over 65,000 stores including Whole Foods Market, Sprouts, Safeway / Albertsons, Kroger, Publix, and Target. All Health-Ade products are naturally fermented with high-quality ingredients and are certified organic, non-GMO, gluten-free and vegan, and each bottle of Health-Ade Kombucha exceeds the World Health Organization’s daily standard for probiotics.

SOURCE Health-Ade

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