Health
What Enables Herpes Simplex Virus To Become Impervious to Drugs?
Research pinpoints key to the cold sore virus’s ability to evade treatment, offering broader clues on antiviral drug resistance
Newswise — All organisms — from fungi to mammals — have the capacity to evolve and adapt to their environments. But viruses are master shapeshifters with an ability to mutate greater than any other organism. As a result, they can evade treatments or acquire resistance to once-effective antiviral medications.
Is the Herpes Simplex Virus Becoming Impervious to Drugs?
Working with herpes simplex virus (HSV), a new study led by Harvard Medical School researchers sheds light on one of the ways in which the virus becomes resistant to treatment, a problem that could be particularly challenging among people with compromised immune function, including those receiving immune-suppressive treatment and those born with immune deficiencies.
Using a sophisticated imaging technique called cryogenic electron microscopy (cryo-EM), the researchers found that how parts of a protein responsible for viral replication move into different positions can alter the virus’s susceptibility to medicines.
The findings, published Aug. 27 in Cell, answer long-standing questions about why certain viruses, but not others, are susceptible to antiviral medications and how viruses become impervious to drugs. The results could inform new approaches that impede viruses’ capacity to outpace effective therapies.
Counterintuitive results
Researchers have long known changes that occur on the parts of a virus where antiviral drugs bind to it can render it resistant to therapy. However, the HMS researchers found that, much to their surprise, this was often not the case with HSV.
Instead, the investigators discovered that protein mutations linked to drug resistance often arise far from the drug’s target location. These mutations involve alterations that change the movements of a viral protein, or enzyme, that allows the virus to replicate itself. This raises the possibility that using drugs to block or freeze the conformational changes of these viral proteins could be a successful strategy for overcoming drug resistance.
“Our findings show that we have to think beyond targeting the typical drug-binding sites,” said the study’s senior author, Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at HMS and infectious disease specialist at Brigham and Women’s Hospital. “This really helps us see drug resistance in a new light.”
The new findings propel the understanding of how alterations in the conformation of a viral protein — or changes in how the different parts within that protein move when it carries out its function — fuel drug resistance and may be relevant for understanding drug effectiveness and drug resistance in other viruses, the researchers noted.
HSV, estimated to affect billions of people worldwide, is most commonly known as the cause of cold sores and fever blisters, but it can also lead to serious eye infections, brain inflammation, and liver damage in people with compromised immunity. Additionally, HSV can be transmitted from mother to baby via the birth canal during delivery and cause life-threatening neonatal infections.
Clues on resistance rooted in structure and movement
A virus can’t replicate on its own. To do so, viruses must enter a host cell, where they unleash their replication tools — proteins called polymerases — to make copies of themselves.
The current study focused on one such protein — a viral DNA polymerase — crucial for HSV’s ability to reproduce and propagate itself. The ability to carry out its function is rooted in the DNA polymerase’s structure, often likened to a hand with three parts: the palm, the thumb, and the fingers, each carrying out critical functions.
Given their role in enabling replication, these polymerases are critical targets of antiviral drugs, which aim to stop the virus from reproducing itself and halt the spread of infection. The HSV polymerase is the target of acyclovir, the leading antiviral drug for treating HSV infection, and of foscarnet, a second-line drug used for drug-resistant infections. Both drugs work by targeting the viral polymerase but do so in different ways.
Scientists have long struggled to fully understand how alterations in the polymerase render the virus impervious to normal doses of antiviral drugs and, more broadly, why acyclovir and foscarnet are not always effective against the altered forms of the HSV polymerase.
“Over the years, the structures of many polymerases from various organisms have been determined, but we still don’t fully understand what makes some polymerases, but not others, susceptible to certain drugs,” Abraham said. “Our study reveals that how the different parts of the polymerases move, known as their conformational dynamics, is a critical component of their relative susceptibility to drugs.”
Proteins, including polymerases, are not rigid, motionless objects. Instead, they are flexible and dynamic.Composed of amino acids, they initially fold into a steady, three‐dimensional shape known as the native conformation — their baseline structure. But as a result of various bonding and dispersing forces, the different parts of proteins can move when they come into contact with other cellular components as well as through external influences, such as changes in pH or temperature. For example, the fingers of a polymerase protein can open and close, as would the fingers of a hand.
Conformational dynamics — the ability of different parts of a protein to move — allow them to efficiently administer many essential functions with a limited number of ingredients. A better understanding of polymerase conformational dynamics is the missing link between structures and functions, including whether a protein responds to a drug and whether it could become resistant to it down the road.
Unraveling the mystery
Many structural studies have captured DNA polymerases in various distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. To solve the puzzle, the researchers carried out a series of experiments, focusing on two common polymerase conformations — an open one and a closed one — to determine how each affects drug susceptibility.
First, using cryo-EM, they conducted structural analysis to get high-resolution visualizations of the atomic structures of HSV polymerase in multiple conformations, as well as when bound to the antiviral drugs acyclovir and foscarnet. The drug-bound structures revealed how the two drugs selectively bind polymerases that more readily adopt one conformation versus another. One of the drugs, foscarnet, works by trapping the fingers of the DNA polymerase so that they are stuck in a so-called closed configuration.
Further, structural analysis paired with computational simulations suggested that several mutations that are distant from the sites of drug binding confer antiviral resistance by altering the position of the polymerase fingers responsible for closing onto the drug to halt DNA replication.
The finding was an unexpected twist. Up until now, scientists have believed that polymerases closed partially only when they attached to DNA and closed fully only when they added a DNA building block, a deoxynucleotide. It turns out, however, that HSV polymerase can fully close just by being near DNA. This makes it easier for acyclovir and foscarnet to latch on and stop the polymerase from working, thus halting viral replication.
“I’ve worked on HSV polymerase and acyclovir resistance for 45 years. Back then I thought that resistance mutations would help us understand how the polymerase recognizes features of the natural molecules that the drugs mimic,” said study co-author Donald Coen, professor of biological chemistry and molecular pharmacology at HMS. “I’m delighted that this work shows that I was wrong and finally gives us at least one clear reason why HSV polymerase is selectively inhibited by the drug.”
Authorship, funding, disclosures
Additional authors included Sundaresh Shankar, Junhua Pan, Pan Yang, Yuemin Bian, Gábor Oroszlán, Zishuo Yu, Purba Mukherjee, David J. Filman, James M. Hogle, Mrinal Shekhar.
This work was supported by the National Institutes of Health (awards R21 AI141940 and R01 AI19838), with additional funding from a Centers for Integrated Solutions in Infectious Diseases grant.
What Enables Herpes Simplex Virus To Become Impervious to Drugs?
Source: Harvard Medical School
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Lifestyle
Get chronic UTIs? Future treatments may add more bacteria to your bladder to beat back harmful microbes
Researchers developed a biomaterial releasing beneficial E. coli to combat urinary tract infections by outcompeting harmful bacteria, aiming to reduce antibiotic resistance and manage chronic UTIs effectively.
Sarguru Subash, Texas A&M University
Millions of people in the U.S. and around the world suffer from urinary tract infections every year. Some groups are especially prone to chronic UTIs, including women, older adults and some veterans.
These infections are typically treated with antibiotics, but overusing these drugs can make the microbes they target become resistant and reduce the medicines’ effectiveness.
To solve this problem of chronic UTIs and antibiotic resistance, we combined our expertise in microbiology and engineering to create a living material that houses a specific strain of beneficial E. coli. Our research shows that the “good” bacteria released from this biomaterial can compete with “bad” bacteria for nutrients and win, dramatically reducing the number of disease-causing microbes.
With further development, we believe this technique could help manage recurring UTIs that do not respond to antibiotics.
Bringing bacteria to the bladder
For the microbes living in people, nutrients are limited their presence varies between different parts of the body. Bacteria have to compete with other microbes and the host to acquire essential nutrients. By taking up available nutrients, beneficial bacteria can stop or slow the growth of harmful bacteria. When harmful bacteria are starved of important nutrients, they aren’t able to reach high enough numbers to cause disease.
Delivering beneficial bacteria to the bladder to prevent UTIs in challenging, though. For one, these helpful bacteria can naturally colonize only in people who are unable to fully empty their bladder, a condition called urinary retention. Even among these patients, how long these bacteria can colonize their bladders varies widely.
Current methods to deliver bacteria to the bladder are invasive and require repeated catheter insertion. Even when bacteria are successfully released into the bladder, urine will flush out these microbes because they cannot stick to the bladder wall.
Biomaterials to treat UTIs
Since beneficial bacteria cannot attach to and survive in the bladder for long, we developed a biomaterial that could slowly release bacteria in the bladder over time.
Our biomaterial is composed of living E. coli embedded in a matrix structure made of gel. It resembles a piece of jelly about 500 times smaller than a drop of water and can release bacteria for up to two weeks in the bladder. By delivering the bacteria via biomaterial, we overcome the need for the bacteria to attach to the bladder to persist in the organ.
We tested our biomaterial by placing it in human urine in petri dishes and exposing it to bacterial pathogens that cause UTIs. Our results showed that when mixed in a 50:50 ratio, the E. coli outcompeted the UTI-causing bacteria by increasing to around 85% of the total population. When we added more E. coli than UTI-causing bacteria, which is what we envision for future development and testing, the proportion of E. coli increased to over 99% of the population, essentially wiping out the UTI-causing bacteria. Moreoever, the biomaterial continued releasing E. coli for up to two weeks in human urine.
Our findings suggest that E.coli could stick around and survive in the bladder for extended periods of time and successfully decrease the growth of many types of bacteria that cause UTIs.
Improving biomaterials
Our findings show that E. coli can not only control harmful bacteria it’s closely related to but also a broad range of disease-causing bacteria in humans and animals. This means scientists might not need to identify different types of beneficial bacteria to control each pathogen – and there are many – that can cause a UTI.
Our team is currently evaluating how effectively our biomaterial can cure UTIs in mice. We are also working to identify the specific nutrients that beneficial and harmful bacteria compete over and what factors may help beneficial bacteria win. We could add these nutrients to our biomaterial to be released or withheld.
This research is still at an early stage, and clinical uses are not in development yet, so if it does reach patients it will be well in the future. We hope that our technology could be refined and applied to control other bacterial infections and some cancers caused by bacteria.
Sarguru Subash, Assistant Professor of Veterinary Pathobiology, Texas A&M University
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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Does Your Favorite Brand of Dark Chocolate Contain Dangerous Metals?
According to a recent article from Consumer Reports, there are some brands of Dark Chocolate that contain dangerous levels of lead, and cadmium.
Dark Chocolate
According to a recent article from Consumer Reports, there are some brands of Dark Chocolate that contain dangerous levels of lead, and cadmium.
Dark Chocolate has become popular due to studies suggesting that they are rich in antioxidants, which is beneficial to the heart, and it having low sugar properties that positively impact health.
The article, which was posted in mid December, states that 28 popular brands were tested, and that 23 of them contained high levels of the dangerous metals.
For more details, check out the article from Consumer Reports: https://www.consumerreports.org/health/food-safety/lead-and-cadmium-in-dark-chocolate-a8480295550/
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Healthy Habits for Your Home
If you’re like most Americans, health is an important aspect of your resolutions when each new year rolls around. While factors like diet and exercise are keys to healthy living, so are the ways you care for your home and belongings.
(Family Features) If you’re like most Americans, health is an important aspect of your resolutions when each new year rolls around. While factors like diet and exercise are keys to healthy living, so are the ways you care for your home and belongings.
Good Habits start at Home
Your home living environment plays a major role in your health and comfort, so incorporating some new habits like these from the cleaning experts at Swash Laundry Detergent can help you establish a healthier lifestyle.
Control Air Quality
Especially during the winter months when your home tends to be closed tight, air can grow stale. Do your best to keep air quality strong by opening windows on mild days to circulate fresh air, using an air purifier to remove irritants and pollutants, frequently vacuuming and sweeping to keep floor dust and debris under control and regularly cleaning textiles that can trap allergens and other particles.
Scale Back Detergent Use
Using too much laundry detergent isn’t just risking buildup and unnecessary wear on your washer and dryer; it can also increase the residue and buildup in your clothes, which can lead to skin irritation and damage fabric faster. Using only what you need helps protect your belongings and your skin. An option like Swash Laundry Detergent, which features a Precision Pour Cap, dispenses the detergent for you, so you only pour what you need to effectively clean each load and fight stains. A single bottle of the ultra-concentrated formula – available in Simply Sunrise, Free & Clear and Pure Linen scents – washes up to 83 loads while taking up less space than traditional, bulky detergent bottles.
Make Use of Natural Light
When winter brings day after day of dark, dreary weather, it can take a toll on your mood. Brightening your living space with natural light can positively influence your emotional state while helping with your electric bill. If you’re concerned about privacy, utilize window treatments at night, but let the sunlight bring good cheer to your living spaces during the day.
Switch Bedding on Schedule
While you sleep, your body sheds oils, cells and elements you carry into your home like pollen. Sheets should be washed once a week on the hottest water setting your fabric will tolerate (check tags for laundering directions on your sheets before washing). If your schedule makes weekly washing, drying and remaking the bed unrealistic, consider having a couple sets you can rotate so you always have fresh, clean sheets waiting to remake your bed on laundry day.
Work Up (and Wash Out) a Sweat
The materials that keep you feeling cool and fresh by wicking away sweat can quickly get stinky, but over-washing can make them lose their shape and fade. Even so, washing after every use is a must. Washing workout clothes inside out exposes the surfaces that have absorbed sweat and body oil to detergent and agitation. Be sure to close zippers, buttons, clasps and other fasteners to prevent snags. Pre-soaking with equal parts vinegar and cold water can also help eliminate odors, and washing in a gentle, cold-water cycle and drying on low heat can help protect the fabric’s elasticity and wicking properties.
Start your year off right with more advice for healthy habits around the home at Swash.com.
5 Ideas for an Organized, Intentional Laundry Space
Having an organized and decorated laundry room can ease the weight of your to-do list and the tension you feel from the day-to-day grind. It can also help keep your laundry routine simple, orderly and organized. Consider these tips from the laundry experts at Swash:
1. Think like a minimalist.
Empty your laundry space and sort through what you need and what you don’t. Eliminating the extras leaves room to evaluate your space. Consider whether you could organize differently to make frequently used items more accessible and make the most of your storage space. Cutting down on clutter may even make it possible to incorporate shelves or cabinets that add stylish functionality.
2. Update your space with open shelving.
Open laundry shelves offer a sense of more space, and the horizontal lines can lend a sense of calm. For an easy and attractive upgrade, try hanging 2-3 open shelves within easy reach. If you’re hesitant about the open feel, limit to just one shelf for the everyday necessities and keep the rest of your laundry supplies out of sight in a complementing cabinet. Baskets offer another option for concealing your belongings, whether you use them on the open shelves or inside cabinets to keep things tidy and clutter-free.
3. Create a practical workspace.
Mundane laundry chores like folding can be more enjoyable when you have a comfortable, dedicated space for the job. An open counter or table that folds down from the wall gives you the surface you need to fold clothing within your laundry space without disrupting the rest of the house. Other ways to add practical space include areas for sorting garments that need special attention and a place to hang items that shouldn’t be dried in the dryer.
4. Use colors and materials that evoke calm.
Natural materials and a neutral color palette can lend to a more peaceful space. Lighter neutral colors reduce stress and anxiety, promote relaxation and can even make a space feel more expansive. For a calm, refreshing area, start with a base of white then add natural textures like woven baskets, faux or real plants and marble stone accents in the tile flooring or backsplash. Add a calming color like blue to evoke the tranquility of the sky or ocean, or consider green to incorporate the soothing effects of nature.
5. Invest in products that bring you joy.
Choose quality pieces that aren’t overly trendy and will stand the test of time. Consider how your investment of laundry decor, including your washer and dryer, will serve you in the space in the coming years.
Photo courtesy of Getty Images (woman making bed)
SOURCE:
Swash
Our Lifestyle section on STM Daily News is a hub of inspiration and practical information, offering a range of articles that touch on various aspects of daily life. From tips on family finances to guides for maintaining health and wellness, we strive to empower our readers with knowledge and resources to enhance their lifestyles. Whether you’re seeking outdoor activity ideas, fashion trends, or travel recommendations, our lifestyle section has got you covered. Visit us today at https://stmdailynews.com/category/lifestyle/ and embark on a journey of discovery and self-improvement.
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