Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

immunology

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus.

Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the bacteria?

The answer is neutrophils, one of the most abundant types of immune cells and foot soldiers against bacterial infections. When neutrophils get into the lungs in people with CF, they change behavior and shut off the expression of genes that would be important for them to combat bacteria. They stay around in the lungs, and release harmful proteins that interfere with other cells’ ability to clean up the bacteria.

Tirouvanziam’s lab has developed a culture system for studying neutrophil behavior, a model for how they act in the lungs. The system makes the neutrophils pass through a layer of lung epithelial cells. Under the influence of lung fluids obtained from CF patients, neutrophils turn what Tirouvanziam calls GRIM (Granule Release, Immunomodulatory, Metabolic). They’re feeding but not fighting: highly metabolically active, but not producing the molecules needed for bactericidal activity.

In a recent paper published in Cell Reports Medicine, researchers show that they can reverse the GRIM fate by applying alpha-amanitin, which blocks RNA transcription, and bring back bactericidal activity. This is a sledgehammer approach, because alpha-amanitin shuts down everything – it’s the toxic ingredient in destroying angel/death cap mushrooms.

Thus, alpha-amanitin would not be appropriate as a therapeutic medication. But it is a tantalizing hint of more specific approaches to come – related papers are on the way, Tirovanziam says. Reviving the anti-bacterial ability of neutrophils should be applicable regardless of the pathogen, and independent of antibiotic resistance, he adds.

“We can steer them in the right direction,” he says. “We are starting to realize that neutrophils have multiple programs and pathways – sort of like T cells. And we can show that it is being exposed to CF lung fluid that makes them go wrong – it’s not intrinsic to the neutrophils.”

The paper also says that scientists in his lab have been separating lung fluids from CF patients into fractions, in order to isolate the molecular entities responsible for steering neutrophils down the wrong path.

The first author of the Cell Reports Medicine paper was former graduate student Camila Margaroli, currently a postdoc at UAB. Tirouvanziam’s lab is part of Emory’s Department of Pediatrics and the Emory-Children’s Healthcare Center for Cystic Fibrosis and Airways Disease Research.

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Emory MVA COVID-19 Vaccine Safe and Effective in Animal Models

Researchers at Yerkes National Primate Research Center, Emory University, have developed a COVID-19 vaccine that has proven safe and effective in mice and monkeys. Results from this National Institute of Allergy and Infectious Diseases (NIAID)-funded study were published online Thursday, Feb. 4 in Immunity.

The Emory MVA COVID-19 vaccine induces protective immunity with the platform of modified vaccinia Ankara (MVA), a harmless version of a poxvirus that is well-known for its use in HIV/AIDS vaccines. Like the Moderna and Pfizer COVID-19 vaccines, the Emory MVA COVID-19 vaccine induces strong neutralizing antibodies, which support the immune system’s ability to fight infections. The Emory MVA COVID-19 vaccine also induces killer CD8 T cells, providing a multi-pronged approach to halting SARS-CoV-2.

In addition, the Emory researchers say the vaccine is easily adaptable to address disease variants and can be used in combination with existing vaccines to improve their ability to combat variants and has the potential to be equally effective with a single dose.

Lead researcher Rama Amara, PhD, built the Emory MVA COVID-19 vaccine based on his more than 20 years of experience working with MVA and animal models to develop an HIV/AIDS vaccine. He and his Yerkes-based research team tested two MVA SARS-CoV-2 vaccines in mice. One of them, MVA/S, used the complete spike protein of coronavirus to induce strong neutralizing antibodies and a strong killer CD8 T cell response against SARS-CoV-2.

“Generating neutralizing antibodies is an important component of a successful COVID-19 vaccine because the antibodies can block the virus from entering the body’s cells,” says Amara, Charles Howard Candler professor of microbiology and immunology at Emory University School of Medicine and a researcher in Yerkes’ Division of Microbiology and Immunology and Emory Vaccine Center. “It’s as important to activate CD8 T cells that can clear infected cells, so this allows us to approach halting the virus two ways simultaneously. The CD8 T cells also provide ongoing value because they are key to working against other variants of the virus, especially if antibodies fail.”

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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.  

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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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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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Several ways to survey for SARS-CoV-2 exposure

How many people out there have been exposed to SARS-CoV-2? It’s a tricky question, once you think about all the people who have experienced COVID-19 symptoms over the last several months, but didn’t go to the hospital. And there’s a murkier penumbra of people who may have fended off the virus with a minor immune skirmish.

A recent Emerging Infectious Diseases paper from Emory investigators includes antibody tests on a group of more than 100 adults in the Atlanta area who experienced mild flu-like symptoms this spring, but couldn’t get tested for SARS-CoV-2 itself.

A sizable fraction (22 to 48 percent, depending on when they provided blood samples) had elevated levels of IgM against the coronavirus. IgM is the “rookie” antibody produced when the immune system is first encountering something, as opposed to the more seasoned IgG, which appears later in an immune response and tended to rise only in people who were hospitalized. The Emory authors came to a conclusion that others are also reaching:

“Examining IgM and IgG against multiple SARS-CoV-2–related antigens may thus better inform natural history and vaccine studies than any one antibody.”

To answer these kinds of questions more comprehensively, investigators will need to go broader. For example, this week the American Red Cross published data on what proportion of its blood donors have antibodies against SARS-CoV-2. About 3 percent of first-time donors did, using their criteria.

For big answers, we can look to studies such as Emory’s COVID-Vu, a nationwide population-based study using antibody and virus tests taken at home. Rollins School of Public Health researchers received a $6.6 million grant to launch the study this summer. This type of study is designed to cover everyone, whether they were sick or not.

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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 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 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

In current vaccine research, adjuvants are no secret

Visionary immunologist Charlie Janeway was known for calling adjuvants – vaccine additives that enhance the immune response – a “dirty little secret.”

Charlie Janeway, MD, in a hat he wore often

Janeway’s point was that foreign antigens, by themselves, were unable to stimulate the components of the adaptive immune system (T and B cells) without signals from the innate immune system. Adjuvants facilitate that help.

By now, adjuvants are hardly a secret, looking at some of the research that has been coming out of Emory Vaccine Center. This week, an analysis by Ali Ellebedy, now at Washington University St Louis, and colleagues showed that in healthy volunteers, the AS03 adjuvant boosted otherwise poor immune responses to a limited dose of the exotic avian flu H5N1, recruiting both memory and naïve B cells. More on that here.

The Moderna SARS-CoV-2 vaccine, which has shown some activity in a small clinical trial here at Emory, has its own kind of adjuvant, since it’s made of both innate-immune-stimulating mRNA and clothed in lipid nanoparticles. Extra adjuvants may come into play later, either with this vaccine or others.

A question we’ve seen many people asking, and discussed on Twitter etc is this: how long does the immunity induced by a SARS-CoV-2 vaccine last? How can we make the immune cells induced by a vaccine stick around for a long time? Read more

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