Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

Raymond Schinazi

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.” 

Read more

Posted on by Quinn Eastman in Immunology Leave a comment

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. 

Posted on by Quinn Eastman in Immunology Leave a comment

Another avenue of HIV trickery reveals opportunity

Emory and University of Rochester researchers have discovered an extra way by which HIV adapts to survive in a hiding spot in the human immune system. The results are published in the Journal of Biological Chemistry.

A team led by Baek Kim from the University of Rochester and Raymond Schinazi from Emory found that when HIV faces a shortage of the building blocks it usually uses to replicate, the virus adapts by using different building blocks. The discovery may offer scientists a new way to try to stop the virus.

One of HIV’s favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris. One can think of macrophages as worker bees: they don’t reproduce because they’re focused on getting stuff done.

Raymond Schinazi, PhD, DSc, is director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research

Normally, HIV uses “dNTPs” (building blocks of DNA), but dNTPs are found at very low levels in macrophages because they’ve stopped dividing and making new DNA. Current drugs generally target dNTPs, and aim at the infection in a different type of cells: T cells.

Macrophages do have high levels of RNA building blocks (“rNTPs”). The team found that HIV uses primarily rNTPs instead of dNTPs to replicate inside macrophages. When the team blocked the ability of the virus to interact with rNTPs, its ability to replicate in macrophages was cut by more than 90 percent.

“The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages,” Kim says. “Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier.”

Compounds that interfere with the use of rNTPs already exist and have been tested as anti-cancer drugs.

“We are now developing new anti-HIV drugs jointly based on this novel approach that are essentially non-toxic and can be used to treat and prevent HIV infections,” Schinazi says.

Baek Kim, PhD

The first authors of the paper are graduate students Edward Kennedy from Rochester and Christina Gavegnano from Emory. Other authors include graduate students Laura Nguyen, Rebecca Slate and Amanda Lucas from Rochester, and postdoc Emilie Fromentin from Emory.

The research was funded by the National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs.

University of Rochester press release

Posted on by Quinn Eastman in Immunology 1 Comment

A family of troublemakers known as XMRV

A long-delayed paper on the connection between chronic fatigue syndrome and XMRV (xenotropic murine leukemia virus-related virus) finally surfaced last week in PNAS. Astute readers may recall that XMRV has also been linked to prostate cancer.

Detecting XMRV in prostate tissue. A variety of assays (neutralizing antibodies, polymerase chain reaction or fluorescence in situ hybridization) may be used to look for XMRV

The twist from last week’s paper is that the NIH/FDA team, led by Harvey Alter, didn’t find viruses all with the same sequence in chronic fatigue patients. Instead, they found a cluster of closely related, but different, viruses. While confusing, these results may explain why tests for the presence of the virus that are based on viral DNA sequences may have generated varying (and conflicting) results. An alternative assay based on antibodies, such as the one urologist John Petros and colleagues at Emory developed, may be useful because it casts a wider net.

Pathologist Hinh Ly has been diving into the XMRV field, with a recent paper in Journal of Virology describing what “gateway” (receptor) molecule the virus uses to sneak into cells and what kinds of cells in the prostate it can infect.

In a collaboration with Ila Singh at the University of Utah, antiviral drug expert Raymond Schinazi has found that a number of drugs active against HIV also stop XMRV. This offers some hope that if doctors can detect members of the XMRV family, and figure out what they’re up to, they might be able to combat the troublemakers as well.

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