A combination immunotherapy of IL-21 and IFN-alpha, when added to antiviral therapy, is effective in generating highly functional natural killer cells that can help control and reduce SIV (simian immunodeficiency virus) in animal models. This finding, from Yerkes National Primate Research Center scientists in collaboration with Institut Pasteur, could be key for developing additional treatment options to control HIV/AIDS.
Antiviral therapy (ART) is the current leading treatment for HIV/AIDS, and is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.
To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates natural killer (NK) cells with impaired functionality. In contrast, natural primate hosts of SIV do not progress to AIDS-like disease. Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.
The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN-alpha to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissues.
“Our results indicate ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD, a senior research specialist and manager of the Paiardini research lab. “These robust NK cell responses helped clear cells in the lymph nodes, which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV.”
HIV treatment has historically focused on the role of T cells in immunity, so harnessing NK cells opens up different avenues.
“This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activities can contribute to controlling the virus,” says Mirko Paiardini, PhD, an associate professor of pathology and laboratory Medicine at Emory University and a researcher at Yerkes. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world.”
A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.
Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.
However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.
“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”
Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigatingblood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.
The Emory laboratories of Keqiang Ye and David Weinshenker recently published a paper on ApoE, the most common genetic risk factor for late-onset Alzheimer’s. The findings, published in Acta Neuropathologica, suggest how the risk-conferring form of ApoE (ApoE4) may exacerbate pathology in the locus coeruleus.
The LC, part of the brainstem, is thought to be the first region of the brain where pathological signs predicting future cellular degeneration show up. The LC (“blue spot”) gets its name from its blue color; it regulates attention, arousal, stress responses and cognition. The LC is also the major site for production of the neurotransmitter norepinephrine.
ApoE, which packages and transports cholesterol, was known to modulate the buildup of the toxic protein fragment beta-amyloid, but this proposed mechanism goes through Tau. Tau is the other pesky protein in Alzheimer’s, forming neurofibrillary tangles that are the earliest signs of degeneration in the brain. Tau pathology correlates better with dementia and cognitive impairments than beta-amyloid, which several proposed Alzheimer’s therapeutics act on.
The new paper shows that ApoE4 inhibits the enzyme VMAT2, which packages norepinephrine into vesicles. As a result, free/unpackaged norepinephrine lingers in the cytoplasm, and forms a harmful oxidative byproduct that triggers enzymatic degradation of Tau. Thus, norepinephrine may have a “too hot to handle” role in Alzheimer’s – with respect to the LC — somewhat analogous to dopamine in Parkinson’s, which has also been observed to form harmful byproducts. Dopamine and norepinephrine are similar chemically and both are substrates of VMAT2, so this relationship is not a stretch.
The Emory results make the case for inhibiting the enzyme AEP (asparagine endopeptidase), also known as delta-secretase, as an approach for heading off Alzheimer’s. AEP is the Tau-munching troublemaker, and is activated by the norepinephrine byproduct DOPEGAL
An alternative approach may be to inhibit monoamine oxidase (MAO-A above) enzymes — several old-school antidepressants are available that accomplish this.
At Emory, Ye’s lab has been tracing connections for AEP/delta-secretase in the last few years, and Weinshenker’s group is expert on all things norepinephrine, so the collaboration makes sense.
Delta-secretase’s name positions it in relation to beta- and gamma-secretase, enzymes for processing APP (amyloid precursor protein) into beta-amyloid, but AEP/delta-secretase has the distinction of having its fingers in both the beta-amyloid and Tau pies.
We have to caution that most of the recent research on delta-secretase has been in mouse models. Ye’s collaborators in China have been testing an inhibitor of delta-secretase in animals but it has not reached human studies yet, he reports. That said, this work has been oriented toward figuring out the web of interactions between known players such as ApoE and Tau, whose importance has been well-established in studies of humans with Alzheimer’s.
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.
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.”
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.
With cold weather approaching, many are digging out old jackets to find that the zippers don’t function as well as they used to. This is a good way to understand disruptions of muscle cell attachment studied by Emory cell biologist Guy Benian’s lab.
“This is yet another example in which research using the model genetic organism C. elegans has led to a new insight applicable to all animals, including humans,” Benian says. “Research on this organism has led to crucial advances in our understanding about development, cell death, aging and longevity, RNAi, microRNAs, epigenetics — and muscle.”
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 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. There are legal experts that can help with injury cases even if it’s after a slip and fall injury.
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.
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
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