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
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
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
A collaboration we wrote about back in 2017, between Emory cell biology chair Gary Bassell and University of Florida neurogeneticist Eric Wang, is taking off.
The National Institute of Neurological Disorders and Stroke has awarded Bassell’s and Wang’s laboratories $2.2 million over five years to examine the neuronal function of Muscleblind-like proteins, which play key roles in myotonic dystrophy.
Gary Bassell and Eric Wang have been collaborating on myotonic dystrophy research
The classic symptom for myotonic dystrophy is having trouble releasing one’s grip on a doorknob, but it is a multi-system disorder, caused by expanded DNA triplet or quadruplet repeats. RNA from the expanded repeats is thought to bind and sequester Muscleblind-like proteins, leading to an impaired process of RNA splicing.
Bassell says the project is expected to clarify how Muscleblind-like proteins regulate RNA localization in neurons and also identify therapeutic targets. In recent years, the DM research community has been paying increasing attention to neurologic symptoms.
Congratulations to the CureGRIN Foundation, which was recently awarded a capacity-building grant from the Chan Zuckerberg Initiative’s Rare as One Network. The Chan Zuckerberg Initiative is giving 30 patient advocacy groups such as CureGRIN $450,000 each over two years.
CureGRIN works closely with Emory pharmacologist Stephen Traynelis, who has been investigating rare genetic disorders affecting NMDA receptors, which play key roles in memory, learning and neuronal development. When NMDA receptor function is perturbed by mutations, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.
For the grant, Traynelis is named as the lead researcher for the CureGRIN Foundation, with Tim Benke of Children’s Hospital Colorado as lead clinician. Traynelis is director of the Center for Functional Evaluation of Rare Variants, which hosted a gathering at Emory Conference Center that brought together several GRIN-oriented patient advocacy groups in September 2019.
An influential theory about the anatomical trajectory of Parkinson’s disease is getting a microbial boost. The idea, first proposed by neuroanatomist Heiko Braak in 2003, is that pathology and neurodegeneration start in the intestines and then travel to the brain. See this article in Scientific American for background.
Illustration showing neurons with Lewy bodies, depicted as small red spheres, which are deposits of aggregated proteins in brain cells
Timothy Sampson, in Emory’s Department of Physiology, was first author on a recent paper in eLife, which explores the idea that prion-like proteins produced by intestinal bacteria can accelerate the aggregation of similar proteins found in our cells. The findings suggest that interventions targeting intestinal bacteria could modulate neurodegeneration.
Sampson, a former Emory graduate student who did postdoctoral work in Sarkis Mazmaniam’s lab at Caltech, says he will continue the project here. He and his colleagues were looking at the interaction between a bacterial protein called Curli – involved in adhesion + biofilms — and the aggregation-prone mammalian protein alpha-synuclein, known as a main component of the Lewy body clumps seen in Parkinson’s. The experiments were in a mouse model of Parkinson’s neurodegeneration, in which human alpha-synuclein is overproduced.
Looking ahead, Sampson says he is interested in what signals from the microbiome may trigger, accelerate or slow synuclein aggregation. He’s also looking at where in the GI tract synuclein begins to aggregate, possibly facilitated by particular cells in the intestine, and whether the observations with alpha-synuclein hold true for other proteins such as amyloid-beta in Alzheimer’s.
A huge cancer genome project has highlighted how DNA that doesn’t code for proteins is still important for keeping our cells on track.
The Pan-Cancer Analysis of Whole Genomes analyzed more than 2,600 tumors from 38 tissues, looking for causative mutations and patterns. Previous work had concentrated on the regions of the genome that code for proteins, but a significant proportion of cancer patients’ tumors don’t carry known “driver” (causative) mutations in protein-coding regions. So this project went out into what used to be called “junk DNA” or the “dark matter” of the genome.
Emory bioinformatics postdoc Matthew Reyna is the first author of one of 23 papers on the PCAWG project, published Feb. 5 in the Nature family of journals. His paper in Nature Communications looks at mutations in non-coding regions of the genome in tumors, analyzing which biological processes are affected.
Some of these were mutations in the promoters of genes encoding well-known cancer suppressors such as p53, but the project also identified new genes containing cancer-driving mutations. A promoter is the stretch of DNA that tells the cell “make RNA copies starting here”.
Reyna contributed to the project while he was at Princeton, working with Benjamin Raphael, and at Emory as well. More recently, he’s been investigating protein-protein interactions with Haian Fu, Andrey Ivanov and others as part of the Cancer Target Discovery and Development (CTD2) project.
In a mouse model of chronic viral infection, there are very few virus-specific killer T cells in the blood, Emory Vaccine Center scientists report in a new paper in PNAS. This has implications for efforts to enhance cancer immunotherapy, because in both chronic viral infection and cancer, the same types of exhausted T cells accumulate.
CD8 T cells in lymphoid tissue (spleen) – from Im et al Nature (2016)
Vaccine Center director Rafi Ahmed’s lab has learned a great deal about exhausted T cells by studying the LCMV (lymphocytic choriomeningitis virus) model. In this situation, virus-specific CD8 T cells accumulate in lymph nodes and in other organs, without circulating in the blood, because they acquire a residency program, the PNAS authors write. Postdoc Sejin Im’s 2016 paper defined these “stem-like” cells – he is the first author of the new one as well.
A related phenomenon can be seen in the Kissick lab’s recent paper on immune “outposts” in kidney and other urologic tumors. The stem-like cells stay within the tumor and give rise to similar progeny. One consequence may be that treatments aimed at reactivating those cells need to get inside the tumor.