Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype. Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients. Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple Read more

Promiscuous protein droplets regulate immune gene activity

Biochemists at Emory are achieving insights into how an important regulator of the immune system switches its function, based on its orientation and local environment. New research demonstrates that the glucocorticoid receptor (or GR) forms droplets or “condensates” that change form, depending on its available partners. The inside of a cell is like a crowded nightclub or party, with enzymes and other proteins searching out prospective partners. The GR is particularly well-connected and promiscuous, and Read more

Neutrophils flood lungs in severe COVID-19

In the lungs of severe COVID-19 patients, neutrophils camp out and release inflammatory cytokines and tissue-damaging Read more

Immunology

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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NIAID long COVID workshop

On Thursday and Friday, Emory researchers participated in an online NIAID workshop about “post-acute sequelae” of COVID-19, which includes people with long COVID.

Long COVID has some similarities to post-viral ME/CFS (myalgic encephalomyelitis/ chronic fatigue syndrome), which has a history of being dismissed or minimized by mainstream medicine. In contrast, the workshop reflected how seriously NIAID and researchers around the world are taking long COVID.

Post-acute is a confusing term, because it includes both people who were hospitalized with COVID-19, sometimes spending weeks on a ventilator or in an intensive care unit, as well as members of the long COVID group, who often were not hospitalized and did not seem to have a severe infection to begin with.

COVID-19 infection can leave behind lung or cardiac damage that could explain why someone would have fatigue and shortness of breath. But there are also signs that viral infection can perturb other systems of the body, leading to symptoms such as “brain fog” (cognitive/memory problems), persistent pain and/or loss of smell and taste.

Highlights from Thursday were appearances from patient advocates Hannah Davis and Chimere Smith, along with virologist Peter Piot, who all described their experiences. Davis is part of a patient-led long COVID-19 support group, which has pushed research forward.

One goal for the workshop was to have experts discuss how to design future studies, or how to take advantage of existing studies to gain insights. A major clue on what to look for comes from Emory immunologist Ignacio Sanz, who spoke at the conference.

Sanz’s research has shown similarities between immune activation in people hospitalized at Emory with severe COVID-19 and in people with the autoimmune disease lupus. In lupus, the checks and balances constraining the immune system break down. A characteristic element of lupus are autoantibodies: antibodies that recognize parts of the body itself. Their presence in COVID-19 may be an explanation for the fatigue, joint pain and other persistent symptoms experienced by some people after their acute infections have passed.

Part of Ignacio Sanz’s talk at the NIAID conference on post-acute sequelae of COVID-19

For details on Sanz’s research, please see our write-up from October, their Nature Immunology paper, and first author Matthew Woodruff’s explainer. The Nature Immunology paper’s results didn’t include measurement of autoantibodies, but a more recent follow-up did (medRxiv preprint). More than half of the 52 COVID-19 patients tested positive for autoantibodies at levels comparable to those in lupus. In those with the highest amounts of the inflammatory marker CRP, the proportion was greater.

“It could be that severe viral illness routinely results in the production of autoantibodies with little consequence; this could just be the first time we’re seeing it,” Woodruff writes in a second explainer. “We also don’t know how long the autoantibodies last. Our data suggest that they are relatively stable over a few weeks. But, we need follow-up studies to understand if they are persisting routinely beyond infection recovery.”

Sanz’s group was looking at patients’ immune systems when both infection and inflammation were at their peaks. They don’t yet know whether autoantibodies persist for weeks or months after someone leaves the hospital. In addition, this result doesn’t say what is happening in the long COVID group, many of whom were not hospitalized.

Autoantibodies have also been detected in MIS-C (multisystem inflammatory syndrome in children), a rare complication that can come after an initial asymptomatic infection. In addition, some patients’ antiviral responses are impaired because of autoantibodies against interferons.

It makes sense that multiple mechanisms could explain post-COVID impairments, including persistent inflammation, damage to blood vessels or various organs, and blood clots/mini-strokes.

Anthony Komaroff from Harvard, who chaired a breakout group on neurology/psychiatry, said the consensus was that so far, direct evidence of viral infection in the brain is thin. Komaroff said that neuro/psych effects are more likely to come from the immune response to the virus.

There were breakout groups for different areas of investigation, such as cardiovascular, and gastrointestinal. Emory Vaccine Center director Rafi Ahmed co-chaired a session for immunologists and rheumatologists, together with Fred Hutch’s Julie McElrath.

Emory’s Carlos del Rio, who recently summarized long COVID for JAMA, spoke about racial and ethnic disparities in COVID-19’s impact and said he expected similar inequities to appear with long COVID.

Reports from the breakout groups Friday emphasized the need to design prospective studies, which would include people before they became sick and take baseline samples. Some suggestions came for taking advantage of samples from the placebo groups in recent COVID-19 vaccine studies.

La Jolla immunologist Shane Crotty said that researchers need to track the relationship between infection severity/duration and post-infection impairments. “There’s a big gap on the virological side,” Crotty said. He noted that one recent preprint shows that SARS-CoV-2 virus is detectable in the intestines in some study participants 3 months after onset.  

Posted on by Quinn Eastman in Immunology 1 Comment

Another side to cancer immunotherapy? Emory scientists investigate intratumoral B cells

Immunotherapies have transformed the treatment of several types of cancer over the last decade. Yet they focus on reactivating one arm of the immune system: cytotoxic T cells, which sniff out and kill tumor cells.

In a new paper in Nature, scientists at Emory Vaccine Center and Winship Cancer Institute of Emory University (Winship) report on their detailed look at B cells’ presence inside tumors. B cells represent the other major arm of the adaptive immune system, besides T cells, and could offer opportunities for new treatments against some kinds of cancers.

“Intratumoral B cells are an area of growing interest, because several studies have now shown that they are associated with a better prognosis and longer survival,” says first author Andreas Wieland, PhD, an Instructor in Rafi Ahmed’s lab at Emory Vaccine Center. “However, nobody really knows what those B cells are specific for.”

Wieland, Ahmed and colleagues decided to concentrate on head and neck cancers that were positive for human papillomavirus (HPV), because the virus provided a defined set of tumor-associated antigens, facilitating the study of tumor-specific B cells across patients.

“Our findings open the door for harnessing this type of cancer-specific immunity in future immunotherapy applications,” says Nabil Saba, MD, director of the head and neck medical oncology program at Winship. “This has implications not just for HPV-related squamous cell carcinomas of the head and neck, but for the broader field of immuno-oncology.”

The Emory Vaccine Center researchers worked with Saba and Winship surgeon Mihir Patel, MD to obtain samples of head and neck tumors removed from 43 patients.

“This has been a wonderful collaborative effort,” Patel adds. “We’re grateful to the patients whose tumor samples contributed to this study, and I’m looking forward to where this information takes us.”

Within HPV-positive tumors, researchers found an enrichment for B cells specific to HPV proteins, and a subset of these cells were actively secreting HPV-specific antibodies. In the tumors, they could see germinal center-like structures, resembling the regions within lymph nodes where B cells are “trained” during an immune response.

Orange represents tumor cells displaying the antigen p16, while green represents B cells, with the arrows indicating germinal center-like structures. Courtesy of Andreas Wieland.

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Saliva-based SARS-CoV-2 antibody testing

As the Atlanta area recovers from Zeta, we’d like to highlight this Journal of Clinical Microbiology paper about saliva-based SARS-CoV-2 antibody testing. It was a collaboration between the Hope Clinic and investigators at Johns Hopkins, led by epidemiologist Christopher Heaney.

Infectious disease specialists Matthew Collins, Nadine Rouphael and several colleagues from Emory are co-authors. They organized the collection of saliva and blood samples from Emory COVID-19 patients at several stages: being tested, hospitalized, and recovered. Saliva samples were collected by having participants brush their gum line with a sponge-like collection device. More convenient than obtaining blood or sticking a swab up the nose!

Saliva collection instrument

The paper shows that antiviral antibody levels in saliva parallel what’s happening in patients’ blood. However, some forms of antibodies (IgM) appear less in saliva because of their greater molecular size. People who test positive do so by 10 days after symptom onset.

The authors conclude: “Saliva-based assays can be used to detect prior SARS-CoV-2 infection with excellent sensitivity and specificity and represent a practical, non-invasive alternative to blood for COVID-19 antibody testing…  A logical next step would be to perform a head-to-head comparison of this novel saliva assay with other antibody tests approved for clinical use.”

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Immune cell activation in severe COVID-19 resembles lupus

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of B cells, resembling acute flares in systemic lupus erythematosus (SLE), an autoimmune disease.

The findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. It also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers – looking similar to what they had observed in SLE.

Update: check out first author Matthew Woodruff’s commentary in The Conversation: “The autoimmune-like inflammatory responses my team discovered could simply reflect a ‘normal’ response to a viral infection already out of hand. However, even if this kind of response is ‘normal,’ it doesn’t mean that it’s not dangerous.”

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

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Many flu viruses needed to crash zoonotic party

With winter on its way, some attention is returning to that other pesky virus: influenza. Emory virologist Anice Lowen and her colleagues recently published a paper in Nature Microbiology highlighting just how inefficient the flu virus is. (Also available on Biorxiv).

It’s not like sperm fertilizing an egg, where one does the trick. Several viral genomes are often required to crash the cellular party. This requirement for multiple genomes may be especially apparent when flu viruses are threatening to cross species barriers – from bird to human, for example.

Multiple infection appears to be more important in this situation!

“An exceptionally high need for multiple infection can occur when an IAV [influenza A virus] infects a new species,” the authors write. “Dependence on multiple infection is of particular interest to cross-species transfer for two reasons: first, it can be overcome in the absence of genetic adaptation through infection at a high dose and second, it leads to high levels of reassortment, which in turn can facilitate adaptation to a new host.”

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High antiviral antibody levels may herald pediatric COVID-19 complication

Measuring blood antibody levels against SARS-CoV-2 may distinguish children with multisystem inflammatory syndrome (MIS-C), which appears to be a serious but rare complication of viral infection, say researchers at Emory University School of Medicine and Children’s Healthcare of Atlanta.  

Children with MIS-C had significantly higher levels of antiviral antibodies – more than 10 times higher — compared to children with milder symptoms of COVID-19, the research team found.  

The results, published in the journal Pediatrics, could help doctors establish the diagnosis of MIS-C and figure out which children are likely to need extra anti-inflammatory treatments. Children with MIS-C often develop cardiac problems and low blood pressure requiring intensive care.

More information about this research here.

Infographic showing CDC criteria for the diagnosis of MIS-C. From Nakra et al via Creative Commons.

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Preparing for weapons production

At Lab Land, we have been thinking and writing a lot about plasma cells, which are like mobile microscopic ar 15 accessories and weapons factories.

Plasma cells secrete antibodies. They are immune cells that appear in the blood (temporarily) and the bone marrow (long-term). A primary objective for a vaccine – whether it’s against SARS-CoV-2, flu or something else — is to stimulate the creation of plasma cells.

A new paper from Jerry Boss’s lab in Nature Communications goes into fine detail on how plasma cells develop. Boss is one of the world authorities on this process. Assistant professor Christopher Scharer and graduate student Dillon Patterson are co-first authors of the paper.

“We are excited about this paper because it shows specific paths and choices that these immune cells make. These previously unknown paths unfold very early in the differentiation scheme as B cells convert their biochemical machinery to become antibody factories,” Boss says. Read more

At Lab Land, we have been thinking and writing a lot about plasma cells, which are like mobile microscopic ar 15 accessories and weapons factories.

Plasma cells secrete antibodies. They are immune cells that appear in the blood (temporarily) and the bone marrow (long-term). A primary objective for a vaccine – whether it’s against SARS-CoV-2, flu or something else — is to stimulate the creation of plasma cells.

A new paper from Jerry Boss’s lab in Nature Communications goes into fine detail on how plasma cells develop. Boss is one of the world authorities on this process. Assistant professor Christopher Scharer and graduate student Dillon Patterson are co-first authors of the paper.

“We are excited about this paper because it shows specific paths and choices that these immune cells make. These previously unknown paths unfold very early in the differentiation scheme as B cells convert their biochemical machinery to become antibody factories,” Boss says. Read more

Posted on by Quinn Eastman in Immunology 1 Comment

SARS-CoV-2 culture system using human airway cells

Journalist Roxanne Khamsi had an item in Wired highlighting how virologists studying SARS-CoV-2 and its relatives have relied on Vero cells, monkey kidney cells with deficient antiviral responses.

Vero cells are easy to culture and infect with viruses, so they are a standard laboratory workhorse. Unfortunately, they may have given people the wrong idea about the controversial drug hydroxychloroquine, Khamsi writes.

In contrast, Emory virologist Mehul Suthar’s team recently published a Journal of Virology paper on culturing SARS-CoV-2 in primary human airway epithelial cells, which are closer to the cells that the coronavirus actually infects “out on the street.”

Effect of interferon-beta on SARS-CoV-2 in primary human epithelial airway cells. Green = SARS-CoV-2, Red = F-actin, Blue = Hoechst (DNA). Courtesy of Abigail Vanderheiden

The Emory researchers found that airway cells are permissive to SARS-CoV-2 infection, but mount a weak antiviral response lacking certain interferons (type I and type III). Interferons are cytokines, part of the immune system’s response to viral infection. They were originally named for their ability to interfere with viral replication, but they also rouse immune cells and bolster cellular defenses.

In SARS-CoV-2 infection, the “misdirected” innate immune response is dominated instead by inflammatory and fibrosis-promoting cytokines, something others have observed as well.

“Early administration of type I or III IFN could potentially decrease virus replication and disease,” the authors conclude. We note that an NIH-supported clinical trial testing a type I interferon (along with remdesivir) for COVID-19 just started.

The first author of the paper is IMP graduate student Abigail Vanderheiden. As with a lot of recent SARS-CoV-2 work, this project included contributions from several labs at Emory: Arash Grakoui’s, Steve Bosinger’s, Larry Anderson’s, and Anice Lowen’s, along with help from University of Texas Medical Branch at Galveston.

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