Engineered “stealth bomber” virus could be new weapon against metastatic cancer

Researchers at Emory and Case Western Reserve have re-engineered a cancer-killing virus, so that it is not easily caught by parts of the immune system. Read more

Another side to cancer immunotherapy? Emory scientists investigate intratumoral B cells

B cells represent the other major arm of the adaptive immune system, besides T cells, and could offer opportunities for new treatments against some kinds of Read more

Don’t go slippery on me, tRNA

RNA can both carry genetic information and catalyze chemical reactions, but it’s too wobbly to accurately read the genetic code by itself. Enzymatic modifications of transfer RNAs – the adaptors that implement the genetic code by connecting messenger RNA to protein – are important to stiffen and constrain their interactions. Biochemist Christine Dunham’s lab has a recent paper in eLife showing a modification on a proline tRNA prevents the tRNA and mRNA from slipping out Read more

Department of Pediatrics

Engineered “stealth bomber” virus could be new weapon against metastatic cancer

Many cancer researchers can claim to have devised “smart bombs.” What has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defenses. 

Oncolytic viruses, or viruses that preferentially kill cancer cells, have been discussed and tested for decades. An oncolytic virus against melanoma was approved by the FDA in 2015. But against metastatic cancers, they’ve always faced an overwhelming barrier: the human immune system, which quickly captures viruses injected into the blood and sends them to the liver, the body’s garbage disposal.

Researchers at Emory and Case Western Reserve have now circumvented that barrier. They’ve re-engineered human adenovirus, so that the virus is not easily caught by parts of the innate immune system.

The re-engineering makes it possible to inject the virus into the blood, without arousing a massive inflammatory reaction.

A cryo-electron microscopy structure of the virus and its ability to eliminate disseminated tumors in mice were reported on November 25 in Science Translational Medicine.

“The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously,” says lead author Dmitry Shayakhmetov, PhD. “For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth — without triggering life-threatening systemic toxicities.”

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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.

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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.

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To fight cancer, mix harmless reovirus with ‘red devil’

A recent paper in Journal of Virology mixes tried-and-true cancer-fighting tactics with the exotic. Sort of a peanut-butter-and-chocolate story, but definitely not tasty!

The tried and true is doxorubicin (Adriamycin), the notorious ‘red devil’ chemotherapy drug, which has been around for decades. On the exotic side, we have oncolytic viruses – viruses retuned to attack cancer cells more than healthy cells. This idea finally made it to FDA approval in 2015 in the form of a re-engineered herpes virus directed against melanoma.

Bernardo Mainou’s lab in the Department of Pediatrics is combining both of these approaches together. He and his team are looking to supercharge reoviruses, a mostly harmless type of virus that has been adapted into an anticancer agent. A Canadian company has brought its reovirus forward into several cancer clinical trials, but its product has not gotten to the finish line.

In the JVI paper, graduate students Roxana Rodriguez-Stewart, Jameson Berry and their colleagues infected triple-negative breast cancer cells with a variety of reoviruses, in an effort to select for those that replicate better in those cells. They also looked for drugs that enhance viral infection of those cells, and landed on doxorubicin and related drugs. Doxorubicin is part of a class of anticancer drugs that inhibit topoisomerases, enzymes that unwind DNA as part of the process of replication.

Yesterday at the GDBBS graduate research symposium, Berry gave a talk about the next step: attaching the souped-up reovirus to doxorubicin.

Three varieties of reovirus were grown together in breast cancer cells to select for efficient replication. 

 

 

 

 

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Microbiome critical for bone hormone action

Intestinal microbes are necessary for the actions of an important hormone regulating bone density, according to two papers from the Emory Microbiome Research Center. The papers represent a collaboration between Roberto Pacifici, MD and colleagues in the Department of Medicine and laboratory of Rheinallt Jones, PhD in the Department of Pediatrics.

Together, the results show how probiotics or nutritional supplementation could be used to modulate immune cell activity related to bone health. The two papers, published in Nature Communications and Journal of Clinical Investigation, are the first reports of a role for intestinal microbes in the mechanism of action of PTH (parathyroid hormone), Pacifici says.

PTH increases calcium levels in the blood and can either drive bone loss or bone formation, depending on how it is produced or administered. Continuous excessive production of PTH, or primary hyperparathyroidism, is a common endocrine cause of osteoporosis. Yet in another context, intermittent external PTH stimulates bone formation, and is an FDA-approved treatment for osteoporosis – also used off-label for fracture repair in athletes. Read more

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Model of a sticky situation

Here’s an example of how 3D printing can be applied to pediatric cardiology. It’s also an example of how Georgia Tech, Emory and Children’s Healthcare of Atlanta all work together.

Biomedical engineers used a modified form of gelatin to create a model of pulmonary arteries in newborn and adolescent patients with a complex (and serious) congenital heart defect: tetralogy of Fallot with pulmonary atresia. The model allowed the researchers to simulate surgical catheter-based intervention in vitro.

The results were recently published in Journal of the American Heart Association. Biomedical engineer Vahid Serpooshan and his lab collaborated with Sibley Heart Center pediatric cardiologist Holly Bauser-Heaton; both are part of the Children’s Heart Research and Outcomes Center.

“This is a patient-specific platform, created with state-of-the-art 3D bioprinting technology, allowing us to optimize various interventions,” Serpooshan says.

Model of an adolescent patient’s pulmonary arteries, created by 3D printing. From Tomov et al JAHA (2019) via Creative Commons

 

 

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Powerful opioids + kids: bad combo

New research demonstrates the dangers of having powerful opioids such as fentanyl around children and adolescents. National Poison Data System reports show that many are ingesting the drugs unintentionally, but particularly concerning is a rise in the proportion of suspected suicides.

Among children, the proportion of opioid poisonings resulting in admission to a hospital critical care unit has increased since 2005, according to an analysis by Emory and Children’s Healthcare of Atlanta doctors.

Megan Land, MD, Jocelyn Grunwell, MD, PhD and colleagues in the Division of Critical Care in the Department of Pediatrics conducted the research, which is published in the journal Clinical Toxicology.

In a December 20 broadcast, critical care fellow Land told NPR’s Rhitu Chatterjee about her encounter with a child with severe respiratory distress as a result of consuming a fentanyl patch. Grunwell has previous experience studying pediatric intensive care admissions procedures and poisonings.

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Overcoming cardiac pacemaker “source-sink mismatch”

Instead of complication-prone electronic cardiac pacemakers, biomedical engineers at Georgia Tech and Emory envision the creation of “biological pacemakers.” Hee Cheol Cho and colleagues have been taking advantage of his work on a gene called TBX18 that can reprogram heart muscle cells into specialized pacemaker cells.

Graduate student Sandra Grijalva in lab

Every heartbeat originates from a small group of cells in the heart called the sinoatrial node. How these cells drive contractions in the relatively massive, and electrically sturdy, rest of the heart is a problem cardiology researchers call the “source-sink mismatch.” Until Cho’s innovations, it was only possible to isolate a handful of pacemaker cells from animal hearts, and the isolated cells could not be cultured.

Cho and colleagues recently published a paper in Advanced Science describing TBX18-induced pacemaker cell spheroids, a platform for studying source-sink mismatch in culture

Graduate student Sandra Grijalva is the first author of the paper. We first spotted Grijalva’s work when it was presented at the American Heart Association meeting in 2017. Read more

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Fetal alcohol cardiac toxicity – in a dish

Alcohol exposure is known to perturb fetal heart development; half of all children with fetal alcohol syndrome have congenital heart defects, such as arrhythmias or structural abnormalities. Chunhui Xu and colleagues recently published a paper in Toxicological Scienceson how human cardiac muscle cells, derived from iPS (induced pluripotent stem cells), can be used as a model for studying the effects of alcohol.

Alcohol-induced cardiac toxicity is usually studied in animal models, but human cells are different, and a cell-culture based approach could make it easier to study the effects of alcohol and possible interventions more easily.

Red shows toxic effects of alcohol on iPS-derived cardiomyocytes

Xu and her colleagues observed that high levels of alcohol damaged cardiac muscle cells and put them under oxidative stress. But even at relatively low concentrations of alcohol, the researchers also saw perturbations in cells’ electrical activity and the ability to contract, which reasonably matches the effects of alcohol on human heart development. The lowest level tested was 17 millimolar – the legal limit for driving in most states (0.08% blood alcohol content). Read more

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Sifting through signs of inflammation to analyze causes of Crohn’s disease

When studying Crohn’s disease – an inflammatory disorder of the gastrointestinal tract, a challenge is separating out potential causes from the flood of systemic inflammation inherent in the condition. Researchers led by Subra Kugathasan, MD recently published an analysis that digs under signs of inflammation, in an effort to assess possible causes.

Graduate student Hari Somineni, in Kugathasan’s lab, teamed up with Emory and Georgia Tech geneticists for a sophisticated approach that may have found some gold nuggets in the inflammatory gravel. The results were published in the journal Gastroenterology.

In studying Crohn’s disease, Emory + Georgia Tech researchers may have found some gold nuggets in the inflammatory gravel.

The group looked at DNA methylation in blood samples from pediatric patients with Crohn’s disease, both at diagnosis and after treatment and follow-up. The information came from blood samples from 164 children with Crohn’s disease and 74 controls, as part of the RISK study, which is supported by the Crohn’s & Colitis Foundation and Kugathasan leads.

DNA methylation is a dynamic process that can influence molecular phenotypes of complex diseases by turning the gene(s) on or off. The researchers observed that disrupted methylation patterns at the time of diagnosis in pediatric Crohn’s disease patients returned to those resembling controls following treatment of inflammation

“Our study emphasized how important it is to do longitudinal profiling – to look at the patients before and after treatment, rather than just taking a cross section,” Somineni says.

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