Study finds ‘important implications’ to understanding immunity against COVID-19

New research from Emory University indicates that nearly all people hospitalized with COVID-19 develop virus-neutralizing antibodies within six days of testing positive. The findings will be key in helping researchers understand protective immunity against SARS-CoV-2 and in informing vaccine development. The test that Emory researchers developed also could help determine whether convalescent plasma from COVID-19 survivors can provide immunity to others, and which donors' plasma should be used. The antibody test developed by Emory and validated Read more

Emory plays leading role in landmark HIV prevention study of injectable long-acting cabotegravir

Emory University played a key role in a landmark international study evaluating the safety and efficacy of the long-acting, injectable drug, cabotegravir (CAB LA), for HIV prevention. The randomized, controlled, double-blind study found that cabotegravir was 69% more effective (95% CI 41%-84%) in preventing HIV acquisition in men who have sex with men (MSM) and transgender women who have sex with men when compared to the current standard of care, daily oral emtricitabine/tenofovir disoproxil fumarate Read more

Yerkes researchers find Zika infection soon after birth leads to long-term brain problems

Researchers from the Yerkes National Primate Research Center have shown Zika virus infection soon after birth leads to long-term brain and behavior problems, including persistent socioemotional, cognitive and motor deficits, as well as abnormalities in brain structure and function. This study is one of the first to shed light on potential long-term effects of Zika infection after birth. “Researchers have shown the devastating damage Zika virus causes to a fetus, but we had questions about Read more

Department of Pathology and Laboratory Medicine

Some types of intestinal bacteria protect the liver

Certain types of intestinal bacteria can help protect the liver from injuries such as alcohol or acetaminophen overdose, according to Emory scientists led by pathologist Andrew Neish and physiologist Dean Jones.

The research was published on March 25 in Cell Metabolism.

“The composition of the microbiota, because of natural variation, dysbiosis, or supplementation with probiotics, can strongly affect how the liver processes both toxins and pharmacological agents, and thus have clinical consequences on how individuals respond to such exogenous chemicals,” Neish says.

While pretreatment with bacteria is needed for the observed effect in acute liver injury, probiotics or small molecule substitutes may be useful in the treatment of chronic liver diseases, the authors suggest.

In mice, oral administration of Lactobacillus rhamnosus or LGG could protect against liver damage brought on by alcohol or acetaminophen. Several labs had already observed a beneficial effect from LGG against liver injury, but the Emory research establishes an additional mechanism.

The protection comes from a small molecule metabolite produced by the bacteria called 5-MIAA (5-methoxyindoleacetic acid), activating the mammalian transcription factor Nrf2. Other types of bacteria did not produce 5-MIAA or activate Nrf2. While LGG is also known to improve the barrier function of the gut and dampen inflammation, liver-specific depletion of Nrf2 prevented LGG’s beneficial effects, suggesting that this is the primary mechanism of action. Read more

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Can blood from coronavirus survivors save the lives of others?

Donated blood from COVID-19 survivors could be an effective treatment in helping others fight the illness – and should be tested more broadly to see if it can “change the course of this pandemic,” two Emory pathologists say.

The idea of using a component of survivors’ donated blood, or “convalescent plasma,” is that antibodies from patients who have recovered can be used in other people to help them defend against coronavirus.

Emory pathologists John Roback, MD, PhD and Jeannette Guarner, MD, wrote about the prospects of using the donated blood in a commentary published in JAMA. Their article accompanied a small study in China of five patients on ventilators whose condition improved after they were treated with convalescent plasma.

“Deploying passive antibody therapies against the rapidly increasing number of COIVD-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent,” the two wrote. “If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.”

The patients in Shenzhen were also treated with other antiviral and antiinflammatory agents, and the study was too small to come to definite conclusions. Still, the Emory authors say, the Shenzhen study provides an example of an approach that should be tested on a larger scale. Read more

Posted on by Wayne Drash in Immunology, Uncategorized Leave a comment

Immunotherapy combo achieves reservoir shrinkage in HIV model

Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV (simian immunodeficiency virus)-infected nonhuman primates treated with antiviral drugs, Emory researchers and their colleagues have concluded. The reservoir includes immune cells that harbor virus despite potent antiviral drug treatment.

The findings, reported in Nature Medicine, have important implications for the quest to cure HIV because reservoir shrinkage has not been achieved consistently before. However, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Finding an HIV cure is important because, although antiretroviral therapy can reduce the amount of circulating virus to undetectable levels, problematic issues remain such as social stigma in addition to the long-term toxicity and cost of antiretroviral drugs.

“It’s a glass-half-full situation,” says senior author Mirko Paiardini, PhD. “We concluded immune checkpoint blockade, even a very effective combination, is unlikely to achieve viral remission as a standalone treatment during antiretroviral therapy.”

He adds the approach may have greater potential if combined with other immune-stimulating agents. Or it could be deployed at a different point — when the immune system is engaged in fighting the virus, creating a target-rich environment. Other HIV/AIDS researchers have started to test those tactics, he says.

Paiardini is an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. The study performed in nonhuman primates, considered the best animal model for HIV studies, was carried out in collaboration with co-authors Shari Gordon and David Favre at the University of North Carolina at Chapel Hill and GlaxoSmithKline; Katharine Bar at the University of Pennsylvania; and Jake Estes at Oregon Health & Science University. Read more

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FMT microbial transplant for C diff gaining acceptance

In February, the Infectious Diseases Society of America issued new guidelines for fighting Clostridium difficile, the hardy bacterium that can cause life-threatening diarrhea and whose dominance is sometimes a consequence of antibiotic treatment. The guidelines recommend for the first time that FMT (fecal microbiota transplant) be considered for individuals who have repeatedly failed standard antibiotics.

In a nice coincidence, Emory FMT specialists Colleen Kraft and Tanvi Dhere recently published a look at their clinical outcomes with C diff going back to 2012, in Clinical Infectious Diseases. They report 95 percent of patients (122/128) indicated they would undergo FMT again and 70 percent of the 122 said they would prefer FMT to antibiotics as initial treatment if they were to have a recurrence. Read more

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Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

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Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

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Amyloid vs tau? With this AD target, no need to choose

Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.

Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.

In mice, inhibiting AEP hits two targets (amyloid and tau) with one shot

Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.

That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.

Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart. Read more

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Fecal transplant replants microbial garden

When facing a life-threatening infection, the “yuck factor” is a minor concern. Fecal microbiota transplant (FMT for short) has become an accepted treatment for recurrent Clostridium difficile infection, which can cause severe diarrhea and intestinal inflammation.

In a new video, Emory physicians Colleen Kraft and Tanvi Dhere explain how FMT restores microbial balance when someone’s internal garden has been disrupted.

C. difficile or “C diff” is a hardy bacterium that can barge into the intestines after another infection has been treated with antibiotics, when competition for real estate is low. In the last few years, doctors around the world have shown that FMT can resolve recurrent C diff infection better than antibiotics alone.

At Emory, Kraft and Dhere have performed almost 300 FMTs and report a 95 percent success rate when treating recurrent C diff. They have established a standard slate of stool donors, whose health is carefully screened.

Building on their experience with the procedure, Kraft and Dhere are studying whether FMT can head off other antibiotic-resistant infections besides C diff in kidney transplant patients. They have teamed up with infectious disease specialists Aneesh Mehta and Rachel Friedman-Moraco to conduct this study. Read more

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