Quinn Eastman

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

Engineered “stealth bomber” virus could be new weapon against metastatic cancer

Many cancer researchers can claim to have devised “smart bombs.” What has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defenses. 

Oncolytic viruses, or viruses that preferentially kill cancer cells, have been discussed and tested for decades. An oncolytic virus against melanoma was approved by the FDA in 2015. But against metastatic cancers, they’ve always faced an overwhelming barrier: the human immune system, which quickly captures viruses injected into the blood and sends them to the liver, the body’s garbage disposal.

Researchers at Emory and Case Western Reserve have now circumvented that barrier. They’ve re-engineered human adenovirus, so that the virus is not easily caught by parts of the innate immune system.

The re-engineering makes it possible to inject the virus into the blood, without arousing a massive inflammatory reaction.

A cryo-electron microscopy structure of the virus and its ability to eliminate disseminated tumors in mice were reported on November 25 in Science Translational Medicine.

“The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously,” says lead author Dmitry Shayakhmetov, PhD. “For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth — without triggering life-threatening systemic toxicities.”

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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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Don’t go slippery on me, tRNA

RNA can both carry genetic information and catalyze chemical reactions, but it’s too wobbly to accurately read the genetic code by itself. Enzymatic modifications of transfer RNAs – the adaptors that implement the genetic code by connecting messenger RNA to protein – are important to stiffen and constrain their interactions.

Biochemist Christine Dunham’s lab has a recent paper in eLife showing a modification on a proline tRNA prevents the tRNA and mRNA from slipping out of frame. The basics of these interactions were laid out in the 1980s, but the Dunham lab’s structures provide a comprehensive picture with mechanistic insights.

The mRNA code for proline is CCC – all the nucleotides are the same — so it is susceptible to frameshifting.

The paper includes videos that virtually unwrap the RNA interactions. The X-ray crystal structures indicate that tRNA methylation – a relatively small bump — at position 37 influences interactions between the tRNA and the ribosome.

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Two birds with one stone: amygdala ablation for PTSD and epilepsy

The amygdala is a region of the brain known for its connections to emotional responses and fear memories, and hyperreactivity of the amygdala is associated with symptoms of PTSD (post-traumatic stress disorder). That said, it’s quite a leap to design neurosurgical ablation of the amygdala to address someone’s PTSD. This type of irreversible intervention could only be considered because of the presence of another brain disorder: epilepsy.

In a case series published in Neurosurgery, Emory investigators describe how for their first patient with both refractory epilepsy and PTSD, observations of PTSD symptom reduction were fortuitous. However, in a second patient, before-and-after studies could be planned. In both, neurosurgical ablation of the amygdala significantly reduced PTSD symptoms as well as reducing seizure frequency.

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Seeing the value: prostate cancer imaging agent developed at Winship

A study from Winship Cancer Institute of Emory University has the potential to change how patients whose prostate cancer recurs after prostatectomy are treated. The study was featured in both the plenary session and press program of the American Society for Radiation Oncology (ASTRO) Annual Meeting on Monday, October 26.

The Emory Molecular Prostate Imaging for Radiotherapy Enhancement, or EMPIRE-1 trial (NCT01666808), is the first randomized trial of men with prostate cancer with recurring cancer to show that treatment based on advanced molecular imaging can improve disease-free survival rates. The molecular imaging used in the study, the radiotracer fluciclovine (18F) PET, was invented and developed at Emory and Winship.

The phase II/III trial was led by Winship radiation oncologist and prostate cancer specialist Ashesh B. Jani, MD, MSEE, FASTRO, and Winship nuclear radiology specialist David M. Schuster, MD, FACR. The trial enrolled 165 patients whose cancer recurred after having undergone prostatectomies. One group received radiation therapy based on conventional imaging. The other group received treatment that was finalized based on imaging with the fluciclovine PET radiotracer. Those whose treatment was adjusted according to the results of the advanced molecular imaging showed an improvement in the cancer control end point.

“At three years, the group getting treatment guided by PET fluciclovine had a 12 percent better cancer control rate, and this persisted at four years as well, with a 24% improvement,” says Jani. “We think the improvement was seen because the novel PET allowed for better selection of patients for radiation, better treatment decisions, and better radiation target design.”

Fluciclovine PET imaging has been getting some attention in the urology/prostate cancer world.

More details here.

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Unusual partnership may drive neurodegeneration in Alzheimer’s

Emory researchers have gained insights into how toxic Tau proteins kill brain cells in Alzheimer’s disease and other neurodegenerative diseases. Tau is the main ingredient of neurofibrillary tangles, one of two major hallmarks of Alzheimer’s.

Pathological forms of Tau appear to soak up and sequester a regulatory protein called LSD1, preventing it from performing its functions in the cell nucleus. In mice that overproduce a disease-causing form of Tau, giving them extra LSD1 slows down the process of brain cell death.

The results were published on November 2 in Proceedings of the National Academy of Sciences.

Blocking the interaction between pathological Tau and LSD1 could be a potential therapeutic strategy for Alzheimer’s and other diseases, says senior author David Katz, PhD, associate professor of cell biology at Emory University School of Medicine.

“Our data suggest that inhibition of LSD1 may be the critical mediator of neurodegeneration caused by pathological Tau,” Katz says. “Our intervention was sufficient to preserve cells at a late stage, when pathological Tau had already started to form.”

While the Katz lab’s research was performed in mice, they have indications that their work is applicable to human disease. They’ve already observed that LSD1 abnormally accumulates in neurofibrillary tangles in brain tissue samples from Alzheimer’s patients.

First author Amanda
Engstrom, PhD

Mutations in the gene encoding Tau also cause other neurodegenerative diseases such as frontotemporal dementia and progressive supranuclear palsy. In these diseases, the Tau protein accumulates in the cytoplasm in an aggregated form, which is enzymatically modified in abnormal ways. The aggregates are even thought to travel from cell to cell.

Tau is normally present in the axons of neurons, while LSD1 goes to the nucleus. LSD1’s normal function is as an “epigenetic enforcer”, repressing genes that are supposed to stay off.

“Usually LSD1 and Tau proteins would pass each other, like ships in the night,” Katz says. “Tau only ends up in the cytoplasm of neurons when it is in its pathological form, and in that case the ships seem to collide.”

Former graduate student Amanda Engstrom PhD, the first author of the paper, made a short video that explains how she and her colleagues think LSD1 and Tau are coming into contact.

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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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Peeling away pancreatic cancers’ defenses

At Winship Cancer Institute, pancreatic cancer researcher Greg Lesinski and colleagues have a new paper in Molecular Cancer Therapeutics. It’s about a combination immunotherapy approach that gets through pancreatic cancers’ extra defenses, and it represents the preclinical counterpart to a clinical trial that is underway and almost finished at Winship, under the direction of GI oncologist Bassel El-Rayes.

Immunotherapies have transformed how other forms of cancer are treated, but for pancreatic cancers, an obstacle is getting through the dense layers of cellular shielding that the cancers build around themselves. Pancreatic cancers create “nests” of fibrotic stellate cells that pump out inflammatory cytokines such as IL-6.

Pancreatic cancer is anticipated to become the second deadliest cancer in the United States by 2030, surpassing breast and colon cancer. 

“Inflammation and a good immune response don’t always go hand in hand,” El-Rayes told us, for a 2018 Winship magazine article. “High IL-6 causes immune exhaustion, and keeps the good cells out of the tumor.”

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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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