Quinn Eastman

Strengthening SARS-CoV-2 genomic surveillance: support from CDC, private foundations

As part of an effort to strengthen genomic surveillance for emerging strains of SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) has awarded a contract to Emory University researchers to characterize viral variants circulating in Georgia.

The two-year contract is part of the SPHERES (SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance) initiative, with roughly $620,000 in total costs. The principal investigator is Anne Piantadosi, MD, PhD, assistant professor of pathology and laboratory medicine, with co-investigator Mehul Suthar, PhD, assistant professor of pediatrics (infectious diseases).

Both Piantadosi and Suthar are affiliated with Emory University School of Medicine and Emory Vaccine Center. Additional Emory partners include assistant professor of medicine Ahmed Babiker, MBBS, assistant professor of medicine Jesse Waggoner, MD and assistant professor of biology Katia Koelle, PhD.

“We are analyzing SARS-CoV-2 genomes from patients in Georgia to understand the timing and source of virus introduction into our community,” Piantadosi says. “We want to know whether there have been population-level changes in the rates of viral spread, and whether there are associations between viral genotype, viral phenotype in vitro, and clinical phenotype or clinical outcome.”

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Posted on by Quinn Eastman in Immunology, Uncategorized 1 Comment

Emory MVA COVID-19 Vaccine Safe and Effective in Animal Models

Researchers at Yerkes National Primate Research Center, Emory University, have developed a COVID-19 vaccine that has proven safe and effective in mice and monkeys. Results from this National Institute of Allergy and Infectious Diseases (NIAID)-funded study were published online Thursday, Feb. 4 in Immunity.

The Emory MVA COVID-19 vaccine induces protective immunity with the platform of modified vaccinia Ankara (MVA), a harmless version of a poxvirus that is well-known for its use in HIV/AIDS vaccines. Like the Moderna and Pfizer COVID-19 vaccines, the Emory MVA COVID-19 vaccine induces strong neutralizing antibodies, which support the immune system’s ability to fight infections. The Emory MVA COVID-19 vaccine also induces killer CD8 T cells, providing a multi-pronged approach to halting SARS-CoV-2.

In addition, the Emory researchers say the vaccine is easily adaptable to address disease variants and can be used in combination with existing vaccines to improve their ability to combat variants and has the potential to be equally effective with a single dose.

Lead researcher Rama Amara, PhD, built the Emory MVA COVID-19 vaccine based on his more than 20 years of experience working with MVA and animal models to develop an HIV/AIDS vaccine. He and his Yerkes-based research team tested two MVA SARS-CoV-2 vaccines in mice. One of them, MVA/S, used the complete spike protein of coronavirus to induce strong neutralizing antibodies and a strong killer CD8 T cell response against SARS-CoV-2.

“Generating neutralizing antibodies is an important component of a successful COVID-19 vaccine because the antibodies can block the virus from entering the body’s cells,” says Amara, Charles Howard Candler professor of microbiology and immunology at Emory University School of Medicine and a researcher in Yerkes’ Division of Microbiology and Immunology and Emory Vaccine Center. “It’s as important to activate CD8 T cells that can clear infected cells, so this allows us to approach halting the virus two ways simultaneously. The CD8 T cells also provide ongoing value because they are key to working against other variants of the virus, especially if antibodies fail.”

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Memory screening using eye-tracking on mobile devices

Investigators at Emory Brain Health Center have developed a platform for evaluating visual memory, while someone views photos for a few minutes on an iPad.

Emory researchers, led by Goizuieta Alzheimer’s Disease Research Center director Allan Levey and biomedical informatics chair Gari Clifford, are working with the company Linus Health to develop the VisMET (Visuospatial Memory Eye-Tracking Test) technology further. Results from the most recent version were published in the journal IEEE Transaction on Biomedical Engineering, and the Emory/Linus team continues to refine the technology.

The goal is to screen people for memory issues, identifying those with mild cognitive impairment (MCI) or Alzheimer’s disease. The task — difficult to call it a test — was designed to be more efficient, easier to administer, and more enjoyable than tests currently used.

“We think this could be a sensitive and specific method for detecting visual memory impairment, and it’s convenient enough for use on a wider scale,” Levey says.

The VisMET technology is based on this observation. When someone with MCI or Alzheimer’s views a photo twice, and the photo has been changed the second time (example: an object in the scene has been removed), their eyes spend less time checking the new or missing element in the photo, compared with healthy people. This is because the regions of the brain that drive visual memory formation, such as the entorhinal cortex and hippocampus, are some of the earliest to deteriorate in MCI or Alzheimer’s.

Currently, when someone is evaluated for memory loss, they get a battery of “paper and pencil” tests to assess verbal memory. Researchers say the alternative of viewing photos on a tablet could be less intimidating for those taking the test, as well as easier to administer and score. The only instruction given to study participants was to enjoy the images.

“The current way memory tests are implemented can be stressful,” says software engineer Alvince Pongos, who is co-first author of the IEEE TBME paper, now at MIT’s McGovern Institute for Brain Research. “The difficulty of standard memory tests can lead to test-givers repeating task instructions many times, and to test-takers being confused and frustrated. If we design simpler tasks and make our tools available in the comfort of one’s home, then we remove barriers allowing more people to engage with their health information.”

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The blind is off: Moderna COVID-19 vaccine study update

Amidst the tumult in the nation’s capital, a quieter reckoning was taking place this week for the Moderna COVID-19 vaccine clinical trial. Lab Land has been hearing from Emory-affiliated study participants that they’re finding out whether they received active vaccine or placebo.

For example, Emory and Grady physician Kimberly Manning, who had written about her participation in the Moderna study in a Lancet essay, posted on Twitter Tuesday. She discovered she had received placebo, and then was offered active vaccine.

After Moderna reported strong efficacy and an Emergency Use Authorization came from the FDA, this was going to happen at some point – the question was when and how. At the advisory panel hearing in December, there was some tension over whether to remove the blind immediately, as this STAT article describes:

“Companies have said that they feel an ethical obligation to deliver vaccine to placebo recipients; the FDA and experts at its advisory panel have debated whether this obligation even exists. Instead, they argue, offering vaccine to volunteers receiving placebo limits the quality of the data about the vaccine’s long-term efficacy and side effects.”

A plan to keep participants in the study under a blinded crossover design was floated, but not implemented. Some participants have said they sensed from the start, based on temporary unpleasant side effects, whether they had received active vaccine or placebo.

Posted on by Quinn Eastman in Immunology 1 Comment

Combo approach vs drug-resistant fungus

Before 2020 and the COVID-19 pandemic, concern among infectious disease specialists was rising about Candida auris, an emerging fungal pathogen that is often drug-resistant and difficult to eradicate from hospitals.

CDC image of Candida auris

Many people know Candida can cause mouth or vaginal infections and diaper rashes. According to the CDC, Candida also can cause invasive infections in the bloodstream, particularly in hospital or nursing home patients with weakened immune systems. About 30 percent of patients with an invasive Candida infection die – and C. auris is just one particularly hardy variety.

Emory Antibiotic Resistance Center director David Weiss and colleagues have identified a combination of existing antifungal drugs (micafungin and amphotericin B) with enhanced activity against C. auris when used together. The results – in vitro only, so far — were published in a letter to The Lancet Microbe. Postdoctoral fellow Siddharth Jaggavarapu was the first author. Weiss reports his team continues to investigate combination approaches against C. auris.

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Fixing Humpty Dumpty in cancer cells

As Star Trek’s Spock once observed: “As a matter of cosmic history, it has always been easier to destroy than to create.”

The same is true inside human cells, explaining why Emory researchers’ recent accomplishment – finding a small-molecule compound that corrects a defective protein-protein interaction – is so significant for cancer research. It’s like putting Humpty Dumpty back together again.

Xiulei Mo, Haian Fu and colleagues have identified what they call a “mutation-directed molecular glue”. The glue restores a regulatory circuit that when defective, is responsible for acceleration of colorectal and pancreatic cancer. The results are reported in Cell Chemical Biology.

Restoring protein-protein interactions disrupted by an oncogenic mutation is like putting Humpty Dumpty back together again

“It is very exciting, because this is a clear example of a protein-protein interaction stabilizer that can reactivate the lost function and reestablish tumor-suppressive activity,” says Fu, who is chair of Emory’s Pharmacology and Chemical Biology department and leader of Winship Cancer Institute’s Discovery & Developmental Therapeutics program.

Scientists are very good at finding inhibitors for enzymes that are overactive. But they have meager results as far as strengthening interactions that are weak or absent. There are existing examples of drugs that stabilize protein-protein interactions (transplant drugs rapamycin and cyclosporine), but they inhibit the function of the proteins they target, as intended.

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Dissecting atherosclerosis at the single cell level: tasting each piece of a fruit salad

More than a decade ago, Hanjoong Jo and colleagues developed an elegant animal model allowing the dissection of atherosclerosis. It was the first to definitively show that disturbed patterns of blood flow determine where atherosclerotic plaques will later appear.

In atherosclerosis, arterial walls thicken and harden because of a gradual build-up of lipids, cholesterol and white blood cells, which occurs over the course of years in humans. The Jo lab’s model involves restricting blood flow in the carotid artery of mice, which are fed a high-fat diet and also have mutations in a gene (ApoE) involved in processing fat and cholesterol. The physical intervention causes atherosclerosis to appear within a couple weeks. Inflammation in endothelial cells, which line blood vessels, is visible within 48 hours.

The shear-sensitive gene LMO4 is turned on in the middle boxed region, but not the other two, because of disturbed flow in that area of the aorta

Now Jo’s lab has combined the model with recently developed techniques that permit scientists to see molecular changes in single cells. The results were published Tuesday in Cell Reports.

Jo’s lab is in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech.

Previously, when they saw inflammation in blood vessels, researchers could not distinguish between intrinsic changes in endothelial cells and immune or other cells infiltrating into the blood vessel lining.

A video made by Harvard scientists who developed the single cell techniques describes the difference like this. Looking at the molecules in cells with standard techniques is like making a fruit smoothie – everything is blended together. But single cell techniques allow them to taste and evaluate each piece of fruit individually.

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Repurposing a rheumatoid arthritis drug for COVID-19

For COVID-19, many researchers around the world have tried to repurpose drugs for other indications, often unsuccessfully. New clinical trial results show that baricitinib, developed by Eli Lilly and approved for rheumatoid arthritis, can speed recovery and may reduce mortality in some groups of hospitalized COVID-19 patients.

How did this study, sponsored by the National Institute of Allergy and Infectious Diseases, come together? In part, through decade-long groundwork laid by investigators at Emory, and their collaborations with others.

The ACTT-2 results were recently published in New England Journal of Medicine. (More formal NIAID and Emory press releases are here and here.)

For several years, drug hunter and virologist Raymond Schinazi and his team had been investigating a class of medications called JAK inhibitors, as an option for tamping down chronic inflammation in HIV infection. Schinazi was one of the first at Emory to investigate the use of anti-inflammatory agents for herpesviruses and HIV in combination with antiviral drugs. He believed that these viruses “hit and run,” leaving behind inflammation, even if they later go into hiding and seem to disappear.

In Schinazi’s lab, Christina Gavegnano had shown that JAK inhibitors had both anti-inflammatory and antiviral properties in the context of HIV — a project she started as a graduate student in 2010. JAK refers to Janus kinases, which regulate inflammatory signals in immune cells.

 “Our team was working on this for 10 years for HIV,” Gavegnano says. “There was a huge amount of data that we garnered, showing how this drug class works on chronic inflammation and why.” 

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Baricitinib effectively reduces COVID-19 lung inflammation in NHP model

In the race to halt the COVID-19 pandemic, researchers at Yerkes National Primate Research Center of Emory University share two important findings from their latest peer-reviewed, published study in Cell.

Rhesus monkeys are a valid animal model for COVID-19 studies because the way they experience and respond to the virus has comparable similarities to the way the virus affects humans, the researchers say. And baricitinib, an anti-inflammatory medication that is FDA-approved for rheumatoid arthritis, is remarkably effective in reducing the lung inflammation COVID-19 causes when the medication is started early after infection.

The study results have immediate and important implications for treating patients with COVID-19. Baricitinib will be compared against the steroid dexamethasone in a NIAID-sponsored clinical trial called ACTT-4 (Adaptive COVID-19 Treatment Trial), which started in November.

Mirko Paiardini, PhD, a researcher in Yerkes’ Microbiology and Immunology division, and his team selected rhesus macaques as the animal model because they expected the monkeys would mimic the disease course in humans, including the virus traveling to the upper and lower airways, and causing high levels of inflammation in the lungs. The team randomized eight rhesus macaques into two groups – a control and a treatment group; the animals in the treatment group received baricitinib.

“Our results showed the medication reduced inflammation, decreased inflammatory cells in the lungs and, ultimately, limited the virus’ internal path of destruction,” Paiardini says. “Remarkably, the animals we treated with baricitinib rapidly suppressed the processes responsible for inducing lung inflammation, thus elevating baricitinib for consideration as a frontline treatment for COVID-19 and providing insights on the way the drug works and its effectiveness.”

The FDA recently granted baricitinib emergency use authorization in combination with remdesivir based on the results of the ACTT-2 findings. “Our study was under way concurrently and, now, solidifies the importance of baricitinib in treating COVID-19,” Paiardini adds.

Co-senior author Raymond Schinazi, PhD, DSc, inventor of the most commonly used HIV/AIDS drugs to prevent progression of the disease and death, says: “Our study shows the mechanisms of action are consistent across studies with monkeys and clinical trials with humans. This means the nonhuman primate model can provide enough therapeutic insights to properly test anti-inflammatory and other COVID-19 therapies for safety and effectiveness.”

Schinazi is the Frances Winship Walters Professor of Pediatrics at Emory University School of Medicine and is affiliated with Yerkes.

“Ray and his group have been investigating the potential of anti-inflammatory drugs, such as baricitinib, for years in the context of another infection, HIV, in which inflammation is a key cause of sickness and death,” Paiardini says. “Our laboratories have collaborated for years to test therapeutics in the nonhuman primate model of HIV infection, thus placing us in a unique position when COVID-19 hit the U.S. to focus our combined expertise and efforts to halt the virus. It took only a phone call between the two of us to switch gears, begin work to create a reliable and robust monkey model of COVID-19 at Yerkes and test the potential of drugs to block inflammation.”

Tim Hoang, first author and Emory doctoral student in the Immunology and Molecular Pathogenesis Program, says: “It was exciting to be at the forefront of the response to COVID-19 and to be part of this research team that involved collaboration from Yerkes and Emory infectious disease experts, geneticists, chemists, pathologists and veterinarians.”

Co-first author and Emory postdoctoral fellow Maria Pino, PhD, emphasizes: “We knew Yerkes was uniquely suited to conduct this study because of the research and veterinary expertise, specialized facilities and animal colony, and our team’s commitment to providing better treatment options for people who have COVID-19.”

The research team plans to conduct further studies to better understand the inflammation the virus causes and to develop more targeted approached to mitigate the damage COVID-19 leaves behind.

Steven Bosinger, PhD, co-senior author, and his research team conducted the genomic analyses that helped unravel the process by which baricitinib reduces inflammation. “One of the most exciting aspects of this project was the speed genomics brought to the collaborative research,” says Bosinger. “Eight months ago, we began using genomics to accelerate the drug screening process in order to identify treatable, molecular signatures of disease between humans and model organisms, such as the monkeys in this study, In addition to determining the effectiveness of baricitinib, this study highlights Emory researchers’ commitment to improving human health and, in this case, saving human lives.”

Bosinger is assistant professor, Department of Pathology & Laboratory Medicine, Emory School of Medicine (SOM) and Emory Vaccine Center (EVC); director, Yerkes Nonhuman Primate Genomics Core and a researcher in Yerkes’ Division of Microbiology and Immunology. 

Some of the others on the Emory research team include: Arun Boddapati (co-first author), Elise Viox, Thomas Vanderford, PhD, Rebecca Levit, MD, Rafick Sékaly, PhD, Susan Ribeiro, PhD, Guido Silvestri, MD, Anne Piantadosi, MD, PhD, Sanjeev Gumber, BVSc, MVSc, PhD, DACVP, Sherrie Jean, DVM, DACLAM, and Jenny Wood, DVM, DACLAM. Jacob Estes, PhD, at Oregon Health & Science University also collaborated.

Paiardini says, “So many colleagues had a key role in this study. First authors Tim and Maria as well as Yerkes veterinary and animal care personnel who worked non-stop for months on this project. This truly has been a collaborative effort at Emory University to help improve lives worldwide.”

This study was funded by the National Institutes of Health, Emory University’s COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, Yerkes’ base grant, which included support for the center’s Coronavirus Pilot Research Project grants, and Fast Grants.

Grant amounts (direct + indirect) are:

NIH R37AI141258, $836,452/yr (2018-23)

NIH R01AI116379, $783,714/yr (2015-20 + 2021 NCE)

NIH P51 OD011132, $10,540,602/yr (2016-20)

U24 AI120134 $681,214/yr (2020-2025)

S10OD026799 $985,030/yr (2019-2020)

Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, $150,000/1 yr

Fast Grants #2144, $100,000/1 yr

Note: Only a portion of the NIH grant funding was applied to the study reported in this news release. 

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Oxytocin delivery via nanoparticles

The neuropeptide oxytocin, known for promoting social interactions, has attracted interest as a possible treatment for autism spectrum disorder. A challenge is getting the molecule past the blood-brain barrier. Many clinical studies have used delivery via nasal spray, but even then, oxytocin doesn’t last long in the body and shows inconsistent effects.

Emory neuroscientist Andrew Escayg has been collaborating with Mercer/LSU pharmacologist Kevin Murnane on a nanoparticle delivery approach that could get around these obstacles. One of Escayg’s primary interests is epilepsy — specifically Dravet syndrome, a severe genetic form of epilepsy — and oxytocin has previously displayed anti-seizure properties in animal models.

Escayg and Murnane’s recent paper in Neurobiology of Disease shows that when oxytocin is packaged into nanoparticles, it can increase resistance to induced seizures and promote social behavior in a mouse model of Dravet syndrome.

This suggests properly delivered oxytocin could have benefits on both seizures and behavior. In addition to seizures, children and adults with Dravet syndrome often have autism – see this Spectrum News article on the connections.

Escayg reports he is planning a collaboration with oxytocin expert Larry Young at Yerkes, who Tweeted “This is a promising new area of oxytocin research” when the paper was published. Senior postdoc Jennifer Wong has already been working on extending the findings to other mouse models of epilepsy and adding data on spontaneous seizure frequency.

The nanoparticle approach could be used for other neuropeptides such as neuropeptide Y, proposed as a treatment mode for anxiety disorders/PTSD, and hypocretin, the missing molecule in narcolepsy. Murnane formed a company when he was at Mercer to develop the technology.

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