Tweaks to corticosteroids may reduce side effects

Steroid anti-inflammatory drugs such as dexamethasone and prednisone are widely used to treat conditions such as allergies, asthma, autoimmune diseases, cancer – and now, COVID-19. Yet they can have harmful side effects on the skin, bones and metabolism.

The side effects are thought to come from a molecular mechanism that is separate from the anti-inflammatory one, and scientists have envisioned that it may be possible to divide the two. A new paper in PNAS from Emory biochemist Eric Ortlund’s lab sketches out how one potential alternative may work.

Synthetic corticosteroids mimic the action of the stress hormone cortisol; both bind the glucocorticoid receptor (GR) protein. Ortlund’s group obtained structural information on how vamorolone, an experimental drug, sticks to the part of GR that binds hormones.

The American company ReveraGen and Swiss partner Santhera are developing vamorolone for Duchenne muscular dystrophy, but it is possible to envision several other conditions such as ulcerative colitis for which vamorolone or a similar drug could be helpful. Vamorolone is NOT approved by the FDA for Duchenne muscular dystrophy or any other indication.

As far as its interaction with GR, what sets vamorolone apart from conventional corticosteroids is quite subtle: a missing hydrogen bond. This means that GR doesn’t interact as well with various partner proteins, which are needed to turn on genes involved in processes such as metabolism and bone growth. However, the anti-inflammatory effects result mainly from turning inflammatory and immune system genes off, and those interactions are maintained. More on that distinction here and here.

Posted on September 11, 2020 by Quinn Eastman in Uncategorized Leave a comment

Improve old antibiotics rather than discover new ones, BME researchers propose

The resistance of bacteria to antibiotics is a global challenge that has been exacerbated by the financial burdens of bringing new antibiotics to market and an increase in serious bacterial infections as a result of the COVID-19 pandemic.

Biomedical engineering researchers at Georgia Tech and Emory are tackling the problem of antibiotic resistance not by creating new drugs, but by enhancing the safety and potency of ones that already exist.

Aminoglycosides are antibiotics used to treat serious infections caused by pathogenic bacteria like E. coli or Klebsiella. Bacteria haven’t developed widespread resistance to aminoglycosides, as compared to other types of antibiotics. These antibiotics are used sparingly by doctors, in part because of the toxic side effects they can sometimes cause.

In research published in the journal PLOS One, Christopher Rosenberg, Xin Fang and senior author Kyle Allison demonstrated that lower doses of aminoglycosides could be used to treat bacteria when combined with specific metabolic sugars. Low concentrations of antibiotics alone often cannot eliminate dormant, non-dividing bacterial cells, but the researchers hypothesized based on a past study that combining aminoglycosides with metabolites such as glucose, a simple sugar, or mannitol, a sugar alcohol often used as sweetener, could stimulate antibiotic uptake.

The authors tested these treatment combinations against Gram-negative pathogens E. coli, Salmonella and Klebsiella. The results showed that aminoglycoside-metabolite treatment significantly reduced the concentration of antibiotic needed to kill those pathogens. The authors also demonstrated that this treatment combination did not increase bacterial resistance to aminoglycosides and was effective in treating antibiotic-tolerant biofilms, which are bacterial communities that act as reservoirs of infection.

Posted on September 10, 2020 by Quinn Eastman in Uncategorized 1 Comment

Many flu viruses needed to crash zoonotic party

With winter on its way, some attention is returning to that other pesky virus: influenza. Emory virologist Anice Lowen and her colleagues recently published a paper in Nature Microbiology highlighting just how inefficient the flu virus is. (Also available on Biorxiv).

It’s not like sperm fertilizing an egg, where one does the trick. Several viral genomes are often required to crash the cellular party. This requirement for multiple genomes may be especially apparent when flu viruses are threatening to cross species barriers – from bird to human, for example.

Multiple infection appears to be more important in this situation!

“An exceptionally high need for multiple infection can occur when an IAV [influenza A virus] infects a new species,” the authors write. “Dependence on multiple infection is of particular interest to cross-species transfer for two reasons: first, it can be overcome in the absence of genetic adaptation through infection at a high dose and second, it leads to high levels of reassortment, which in turn can facilitate adaptation to a new host.”

Posted on September 9, 2020 by Quinn Eastman in Immunology Leave a comment

High antiviral antibody levels may herald pediatric COVID-19 complication

Measuring blood antibody levels against SARS-CoV-2 may distinguish children with multisystem inflammatory syndrome (MIS-C), which appears to be a serious but rare complication of viral infection, say researchers at Emory University School of Medicine and Children’s Healthcare of Atlanta.

Children with MIS-C had significantly higher levels of antiviral antibodies – more than 10 times higher — compared to children with milder symptoms of COVID-19, the research team found.

The results, published in the journal Pediatrics, could help doctors establish the diagnosis of MIS-C and figure out which children are likely to need extra anti-inflammatory treatments. Children with MIS-C often develop cardiac problems and low blood pressure requiring intensive care.

More information about this research here.

Infographic showing CDC criteria for the diagnosis of MIS-C. From Nakra et al via Creative Commons.

Posted on September 8, 2020 by Quinn Eastman in Immunology 2 Comments

Galanin: the ‘keep calm and carry on’ hormone?

A few celebrity neuropeptides have acquired a reputation – sometimes exaggerated — and a flavor, corresponding to their functions in the brain.

Oxytocin has the aura of a “cuddle hormone” because of its role in social bonding and reproduction. Endorphins are the body’s natural pain-killers, long thought to be responsible for “runner’s high.” Hypocretin/orexin, missing in narcolepsy, is a stabilizer of wakefulness as well as motivation.

Galanin, studied by Emory neuroscientist David Weinshenker’s lab, is not as flashy as other neuropeptides. While it is accumulating an intriguing track record, galanin appears to play subtly different roles depending on where it is expressed. It is tempting to call galanin the “keep calm and carry on” hormone, but the research on galanin is so complex it’s difficult to pin down.

Graduate student Rachel Tillage and colleagues have a paper this week in Journal of Neuroscience detailing how galanin’s production by one group of neurons in the brainstem confers stress resilience in mice.

This image shows the rough location for the locus coeruleus in the human brain. In mice, production of galanin in the locus coeruleus cushions against stress.

The new paper shows that exercise increases galanin in the locus coeruleus, a region in the brainstem that produces norepinephrine (important for attention, alertness, anxiety and muscle tone). Galanin can provide protection against the anxiety-inducing effects of artificial but very specific locus coeruleus activation by optogenetics.

Posted on September 3, 2020 by Quinn Eastman in Uncategorized Leave a comment

Delayed mechanical strain promotes angiogenesis in bone/wound healing

The natural processes of wound or bone healing rely on the growth of new blood vessels, or angiogenesis. If someone breaks a bone, it is standard practice to apply a cast and immobilize the broken bone, so that healing can proceed without mechanical distortion.

After those initial stages of healing, applying surprising amounts of pressure can encourage angiogenesis, according to a new paper in Science Advances from biomedical engineer Nick Willett’s lab.

“These data have implications directly on bone healing and more broadly on wound healing,” Willett says. “In bone healing or grafting scenarios, physicians are often quite conservative in how quickly patients begin to load the repair site.”

Willett’s lab is part of both Emory’s Department of Orthopedics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and is based at the Atlanta Veterans Affairs Medical Center.

Posted on August 21, 2020 by Quinn Eastman in Uncategorized Leave a comment

Burning fat like a baby

Newborn humans and hibernating mammals have high levels of brown adipose tissue, which they use to generate heat. Adult humans generally don’t have abundant brown adipose tissue, even if they have lots of “white” fat. Increasing brown fat’s activity may be an approach to treat obesity and related metabolic disorders.

Recently researchers identified an enzyme called Them1 (thioesterase superfamily member 1) as a factor that limits heat generation in brown adipose tissue. Emory biochemist Eric Ortlund and his lab showed how part of the Them1 enzyme binds a certain type of lipid molecule, and also how that part of the enzyme anchors the enzyme close to lipid droplets in adipose cells. Former graduate student Matt Tillman, now a postdoc at Duke, was the first author of the new paper in Proceedings of the National Academy of Sciences.

“In this study, we show Them1 contains a lipid sensor module that detects specific lipids within the cell to regulate its activity,” says Tillman.

In brown adipose cells, the lipid-sensing domain of Them1 is needed for localization around lipid droplets

From Tillman et al PNAS (2020)

He and his colleagues showed that a lipid known for its role in cell signaling, lysophosphatidylcholine or LPC, inhibits Them1 activity, which in turn activates thermogenesis in brown adipose tissue. In contrast, other fatty acids that serve as fuel tend to activate Them1. This regulatory system within Them1 allows the cell to sense its metabolic state and decide when to burn or conserve fat.

Posted on August 21, 2020 by Quinn Eastman in Uncategorized Leave a comment

Preparing for weapons production

At Lab Land, we have been thinking and writing a lot about plasma cells, which are like mobile microscopic weapons factories.

Plasma cells secrete antibodies. They are immune cells that appear in the blood (temporarily) and the bone marrow (long-term). A primary objective for a vaccine – whether it’s against SARS-CoV-2, flu or something else — is to stimulate the creation of plasma cells.

A new paper from Jerry Boss’s lab in Nature Communications goes into fine detail on how plasma cells develop. Boss is one of the world authorities on this process. Assistant professor Christopher Scharer and graduate student Dillon Patterson are co-first authors of the paper.

“We are excited about this paper because it shows specific paths and choices that these immune cells make. These previously unknown paths unfold very early in the differentiation scheme as B cells convert their biochemical machinery to become antibody factories,” Boss says. Read more

At Lab Land, we have been thinking and writing a lot about plasma cells, which are like mobile microscopic weapons factories.

Posted on August 12, 2020 by Quinn Eastman in Immunology 1 Comment

SARS-CoV-2 culture system using human airway cells

Journalist Roxanne Khamsi had an item in Wired highlighting how virologists studying SARS-CoV-2 and its relatives have relied on Vero cells, monkey kidney cells with deficient antiviral responses.

Vero cells are easy to culture and infect with viruses, so they are a standard laboratory workhorse. Unfortunately, they may have given people the wrong idea about the controversial drug hydroxychloroquine, Khamsi writes.

In contrast, Emory virologist Mehul Suthar’s team recently published a Journal of Virology paper on culturing SARS-CoV-2 in primary human airway epithelial cells, which are closer to the cells that the coronavirus actually infects “out on the street.”

Effect of interferon-beta on SARS-CoV-2 in primary human epithelial airway cells. Green = SARS-CoV-2, Red = F-actin, Blue = Hoechst (DNA). Courtesy of Abigail Vanderheiden

The Emory researchers found that airway cells are permissive to SARS-CoV-2 infection, but mount a weak antiviral response lacking certain interferons (type I and type III). Interferons are cytokines, part of the immune system’s response to viral infection. They were originally named for their ability to interfere with viral replication, but they also rouse immune cells and bolster cellular defenses.

In SARS-CoV-2 infection, the “misdirected” innate immune response is dominated instead by inflammatory and fibrosis-promoting cytokines, something others have observed as well.

“Early administration of type I or III IFN could potentially decrease virus replication and disease,” the authors conclude. We note that an NIH-supported clinical trial testing a type I interferon (along with remdesivir) for COVID-19 just started.

The first author of the paper is IMP graduate student Abigail Vanderheiden. As with a lot of recent SARS-CoV-2 work, this project included contributions from several labs at Emory: Arash Grakoui’s, Steve Bosinger’s, Larry Anderson’s, and Anice Lowen’s, along with help from University of Texas Medical Branch at Galveston.

Posted on August 9, 2020 by Quinn Eastman in Immunology Leave a comment

Triple play in science communication

Emory BCDB graduate student Emma D’Agostino

We are highlighting Emory BCDB graduate student Emma D’Agostino, who is a rare triple play in the realm of science communication.

Emma has her own blog, where she talks about what it’s like to have cystic fibrosis. Recent posts have discussed the science of the disease and how she makes complicated treatment decisions together with her doctors. She’s an advisor to the Cystic Fibrosis Foundation on patient safety, communicating research and including the CF community in the research process. She’s also working in biochemist Eric Ortlund’s lab on nuclear receptors in the liver:drug targets for the treatment of diabetes and intestinal diseases.

The triple play is this — on her blog, Emma has discussed how she has to deal with antibiotic resistance. Emory Antibiotic Resistance Center director David Weiss’ lab has published a lot on colistin: how it’s a last-resort drug because of side effects, and how difficult-to-detect resistance to it is spreading. Emma has some personal experience with colistin that for me, brought the issue closer. Read more

Posted on July 20, 2020 by Quinn Eastman in Uncategorized Leave a comment

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