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

Researchers at Emory and Case Western Reserve have re-engineered a cancer-killing virus, so that it is not easily caught by parts of the immune system. Read more

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

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 Read more

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 Read more

Cancer

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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Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

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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Posted on by Quinn Eastman in Immunology Leave a comment

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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Posted on by Quinn Eastman in Immunology 4 Comments

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

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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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

Posted on by Quinn Eastman in Immunology Leave a comment

Study finds ‘important implications’ to understanding immunity against COVID-19

New research from Emory University indicates that nearly all people hospitalized with COVID-19 develop virus-neutralizing antibodies within six days of testing positive. The findings will be key in helping researchers understand protective immunity against SARS-CoV-2 and in informing vaccine development.

The test that Emory researchers developed also could help determine whether convalescent plasma from COVID-19 survivors can provide immunity to others, and which donors’ plasma should be used.

The antibody test developed by Emory and validated with samples from diagnosed patients has demonstrated that not all antibody tests are created equal – and that neutralizing antibodies, which provide immunity, have specific characteristics. Emory’s study focused on those neutralizing antibodies, which can stop the virus from infecting other cells.

The findings are now available on MedRxiv, the preprint server for health sciences, and are not yet peer-reviewed.

In the study, researchers looked at antibodies against the receptor-binding domain (RBD), part of the spike protein on the outside of the virus. The RBD is what grips on to human cells and allows the virus to enter them. The researchers focused on antibodies against the RBD because the sequence of the RBD in SARS-CoV-2 distinguishes it from other coronaviruses that cause the common cold.

The receptor-binding domain, or RBD, is what grips on to human cells and allows the virus to enter them.

The initial 44 patient blood samples used in this study were from patients being treated for COVID-19 at Emory University Hospital and Emory University Hospital Midtown.

“These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines,” says Mehul S. Suthar, PhD, co-lead author and assistant professor of pediatrics at Emory University School of Medicine and Emory Vaccine Center. This study serves as the initial step in a much larger serology effort.

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Posted on by Wayne Drash in Immunology Leave a comment

Emory launches study on COVID-19 immune responses

Emory University researchers are taking part in a multi-site study across the United States to track the immune responses of people hospitalized with COVID-19 that will help inform how the disease progresses and potentially identify new ways to treat it.  The study is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The study – called Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) – launched Friday. Investigators expect to enroll up to 2,000 individuals who have been hospitalized with the new coronavirus in 10 research locations across the country.

Participants will be followed for up to 12 months after their hospitalization to assess how well they recover and whether they develop durable immunity to the virus.

Nadine Rouphael, associate professor at Emory’s School of Medicine, is leading the investigation as part of NIAID’s Human Immunology Project Consortium (HIPC) and says the study aims to determine how certain immunological measures correspond to or even predict the clinical severity of COVID-19.

“The IMPACC study is a unique opportunity to leverage clinical data and samples with cutting edge technology,” Rouphael says. “By analyzing the immune responses of diverse participants enrolled in the study, we aim to better understand why some cases of COVID-19 worsen while other patients recover.”

As participants recover, investigators will continue evaluating their immune responses to see how they fare: Do they experience lingering symptoms, or do they get long-term protection against the virus? This effort is one of many clinical projects working to better understand how this novel disease affects people differently and determine optimal ways to treat COVID-19.

Researchers will recruit participants within 36 hours of their admission to the hospital and collect blood and nasal swabs throughout their hospitalization, and during follow-up clinic visits after discharge. When possible, researchers will also examine lower airway secretions collected from patients requiring a ventilator for breathing support. Participants can be co-enrolled in other studies, such as those evaluating experimental treatments for COVID-19.

Biologic samples from all study participants will be sent to a number of Core Laboratories for detailed analysis of various aspects of the immune response to the virus that causes COVID-19.

For more information on the U.S. government response to the COVID-19 pandemic, visit www.coronavirus.gov.

Posted on by Wayne Drash in Immunology, Uncategorized Leave a comment
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