Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

immunology

CROI: HIV cure report and ongoing research

The big news out of CROI (Conference on Retroviruses and Opportunistic Infections) was a report of a third person being cured of HIV infection, this time using umbilical cord blood for a hematopoetic stem cell transplant. Emory’s Carlos del Rio gave a nice overview of the achievement for NPR this morning.

As del Rio explains, the field of HIV cure research took off over the last decade after Timothy Brown, known as “the Berlin patient,” was cured after receiving a stem cell transplant for acute myeloid leukemia. His transplant donor had a mutation that made incoming blood and immune cells resistant to HIV infection.

For several reasons – safety, expense, and lack of immune compatibility — it is not practical to do hematopoetic stem cell transplants for everyone infected with HIV. Such transplants, which replace the cells that generate blood and immune cells, pose considerable risk.

“This is not a scaleable intervention,” del Rio told interviewer Leila Fadel. “This is very fascinating science, very cool science that will advance the field of HIV research, but this is also a very rare phenomenon.”

The transplant option comes into consideration when someone living with HIV is diagnosed with leukemia or lymphoma. But the CCR5 delta32 mutation that makes donor cells HIV-resistant is rare and found mainly in people of Northern European descent, and the process of finding a match has limitations. People of color are under-represented in registries for matching donors and recipients.

Using more malleable umbilical cord blood as a source for stem cell transplant may allow the approach to be offered to a larger group of people, including more people of color. Emory’s Vince Marconi told WebMD that cord blood could also allow patients to undergo a less grueling experience.

During the COVID-19 pandemic, the CROI conference has morphed into a premier immunology meeting, including presentations on COVID-19 and SARS-CoV-2, as well as HIV and viral hepatitis. As usual, Emory/Yerkes scientists had a strong presence at CROI.

In particular, researchers such as Mirko Paiardini and Ann Chahroudi have been investigating approaches to HIV/SIV cure in non-human primate models that avoid stem cell transplants. Instead, cancer immunotherapy drugs and HIV “latency reversal” agents (one is called AZD5582) wake up lurking virus-infected immune cells and flush them out. While clinical trials

Paiardini’s upcoming CROI talk on “Novel Immunotherapy-based Cure interventions” is scheduled for this Wednesday. While we can’t reveal the details ahead of time, Paiardini’s colleagues were highly impressed when he gave a presentation about the results in November.

Posted on by Quinn Eastman in Immunology 1 Comment

Report on first Omicron case detected in GA

The first Omicron case detected in Georgia through SARS-CoV-2 genomic surveillance probably became infected during a visit to Cape Town, South Africa, according to a recent case report in Clinical Infectious Diseases.

The patient was a woman in her 30s, who was fully vaccinated with Pfizer/BioNTech twice, then a booster in October 2021 – about six weeks before becoming sick. She had a negative PCR test shortly before traveling back to Georgia but developed symptoms around the time of her return flight.

The woman was diagnosed with COVID-19 at the end of November, a few days after her return to Georgia — just after Omicron was declared a Variant of Concern by the WHO.

This single case report is not representative of the overall severity of Omicron, which is generating a large number of infections, burdening hospitals in Georgia and elsewhere. The patient experienced muscle aches, nausea, fatigue and cough, but did not have a fever or shortness of breath and did not require hospitalization.

A view of Cape Town’s Table Mountain

The lead authors of the case report were Marybeth Sexton, chief quality officer for the Emory Clinic, and infectious disease specialist Jesse Waggoner. The senior author was viral geneticist Anne Piantadosi.

The authors note: “Identifying this case required eliciting an appropriate travel history and being able to identify and perform sequencing for COVID patients in the community, since the patient had mild symptoms and did not seek clinical care.”

To speed detection of SARS-CoV-2 variants such as Omicron, the case report contains information about how to customize the “Spike SNP” PCR assay to give results within a few hours, rather than waiting for full viral sequencing taking 72 hours.

With the help of virologist Mehul Suthar’s lab, the authors were also able to report that the patient developed high levels of antiviral antibodies capable of neutralizing the Omicron variant. Currently available booster shots can elicit measurable antiviral antibody activity (see our recent post Thrice is nice), but actual Omicron infection generates way more.

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Booster COVID-19 vaccine vs Omicron: thrice is nice

A third dose of an mRNA COVID-19 vaccine is necessary to give someone robust neutralizing antibody activity against the Omicron variant, according to data from Emory researchers posted on the preprint server Biorxiv.

The findings support public health efforts to promote booster vaccination as a measure to fight Omicron, which is currently overwhelming hospitals around the world. They also explain why more breakthrough infections are occurring with the Omicron variant in people who have been vaccinated twice, and are in line with what other investigators have observed.

Compared with the 2020 Wuhan strain, the Omicron variant of SARS-CoV2 has more than 30 mutations in the viral spike protein, which is the primary target of neutralizing antibodies generated by vaccination. 

“Our findings highlight the need for a third dose to maintain an effective antibody response for neutralizing the Omicron variant,” says lead author Mehul Suthar, a virologist based at Emory Vaccine Center and Yerkes National Primate Research Center.

Vaccinated individuals who develop breakthrough Omicron infections are likely to experience less severe symptoms, and it is possible for Omicron to infect people even after receiving a booster, Suthar notes. Still, a majority of patients now coming into hospitals continue to be those who are unvaccinated.

In the preprint, Emory researchers tested blood samples from people who participated in Pfizer/BioNTech or Moderna vaccine studies in the laboratory for their ability to smother SARS-CoV-2 variants in culture. The preprint does not include clinical outcomes from infection, and also does not cover other aspects of vaccine-induced antiviral immunity, such as T cells.

In people who were vaccinated twice with mRNA vaccines, either Pfizer/BioNTech or Moderna, none showed measurable neutralizing antibody activity against Omicron six months after vaccination. But 90 percent displayed some neutralizing activity against Omicron a few weeks after a third dose.

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Two items relevant to long COVID

One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater.

A recent report from the United Kingdom, published in PLOS Medicine, studied more than 270,000 people using electronic health records. This research found that more than a third of patients had one or more features of long COVID three to six months after COVID-19 diagnosis.

That would be consistent with recently published findings from Emory, which surveyed 290 people from a telemedicine program: Emory Healthcare’s Virtual Outpatient Management Clinic. Almost 40 percent reported persistent symptoms. However, none of the individual symptoms, such as fatigue, mental fog or difficulty breathing, were reported at a rate of more than about 20 percent.

With this survey, Emory investigators were trying to capture the larger number of people out there who were recovering from COVID-19, without selecting for people who are especially miserable (to put it bluntly). Initial symptom severity predicted the likelihood of long-term symptoms, but there were outliers from this trend. This was a cross-sectional but not longitudinal study. One intriguing finding was that people with hypertension were less likely to experience persistent COVID symptoms, which may have to do with ACE inhibitors, common anti-hypertension drugs.

The second item reports data on autoantibodies from a long COVID cohort at Emory, from immunologists Ignacio Sanz and Eun-Hyung Lee. Autoantibodies are a feature of autoimmune diseases, such as lupus and rheumatoid arthritis, and their presence in long COVID may explain persistent symptoms such as fatigue, skin rash and joint pain.

Several research groups have shown that autoantibodies can result from the intense inflammation of COVID-19 (examples outside Emory here, here), which breaks down the guardrails that normally constrain immune cells from attacking the body itself. But a key question is: how long does that deranged state last? And do autoantibodies correlate with persistent symptoms? This preprint (Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection)– not yet published in a peer review journal — represents the first data on this topic collected from the post-COVID clinics at Emory. More to come on this topic.

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Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009.

Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful.

The researchers think that this signature, observed in immune cells in the blood after vaccination, could be used to design future vaccines that will have a better chance of providing protection against HIV infection.

“We may not need to take ‘shots in the dark’, when testing vaccine platforms or adjuvants for efficacy,” says senior author Rafick-Pierre Sekaly, PhD. “Instead, we can now identify adjuvants and/or vaccine regimens which more potently induce the activation of this signature.”

Rafick-Pierre Sekaly, PhD

The results, published this week in Nature Immunology, also contain hints on a contributing factor explaining why a recent HIV vaccine study conducted in South Africa (HVTN702) did not show a protective effect. HVTN702 was designed as a follow-up to RV144, but multiple parameters were different between the Thai and South African vaccine studies, such as the demographics of the participants, the adjuvant used, and the levels and varieties of HIV circulating.

“Our findings highlight one potential mechanism which may have contributed to the muted efficacy of HVTN702,” says Sekaly, professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.

This mechanism involves the choice of adjuvant, a vaccine additive that enhances immune responses. While RV144 used the adjuvant alum (aluminum hydroxide), HVTN702 used the oil-based adjuvant MF59, also found in some influenza vaccines, to stimulate higher antibody production.

“There are multiple ways that a vaccine can promote protection and some of these do not involve antibodies,” Sekaly says. “Since MF59 failed to potently induce the gene signature we found to be associated with protection, this signature could guide us to mechanisms distinct from antibodies which could trigger protection from HIV-1.”

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COVID-triggered autoimmunity may be mostly temporary

In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the body’s own tissues.

During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered. 

In a preprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.

The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.

During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) – an approach that has been tested on a small scale — may help resolve persistent symptoms, the Emory investigators suggest.

Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.

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Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

A new study reports weakened antibody responses to COVID-19 mRNA vaccines among most patients with multiple myeloma, a form of bone-marrow cancer associated with an immunocompromised state.

The research, published in the journal Leukemia, was carried out at the Institute for Myeloma and Bone Cancer Research (IMBCR) in California, in collaboration with Emory infectious diseases fellow Samuel Stampfer, MD, PhD.

Patients with smoldering myeloma, not requiring treatment, all achieved a good response to COVID-19 vaccination, whereas less than half of patients with active myeloma requiring treatment did. Specifically, only 45 percent of active patients fully responded to the mRNA vaccines, whereas less than a quarter showed a partial response and one-third did not respond to the vaccines above background antibody levels.

Serum samples from 103 multiple myeloma patients were obtained prior to vaccination and 2-3 weeks after administration of the first and second vaccines, and compared to a group of age‑matched healthy controls. Predictors of reduced antibody responses to the vaccines included: older age, impaired renal function, low lymphocyte counts, reduced uninvolved antibody levels, past first line of treatment, and those not in complete remission. Nearly two-thirds of patients who received the Moderna vaccine responded to a level thought to be clinically significant, whereas only approximately a quarter who received the Pfizer vaccine did.

“Based on these data, myeloma patients may need to continue social distancing following COVID-19 vaccination, and postvaccine antibody tests may help guide decisions regarding supplementary vaccination or antibody prophylaxis for this vulnerable population,” says Stampfer, who co-designed the clinical study, under the guidance of senior author James Berenson, MD, the Scientific and Medical Director of IMBCR.

“This study highlights the importance of recognizing the limitations of current vaccination approaches to COVID-19 for immunocompromised patients, and that new approaches will have to be developed to improve their protection from this dangerous infection,” Berenson says. “It also suggests that there may be clinically significant differences in the effectiveness of different COVID-19 vaccines for immune compromised patients. Until these advances occur, it means that myeloma patients will need to remain very careful even if they have been vaccinated through wearing their masks and avoiding contact with unvaccinated individuals.”.

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Natural killer cells can help control virus in primate model of HIV/AIDS

A combination immunotherapy of IL-21 and IFN-alpha, when added to antiviral therapy, is effective in generating highly functional natural killer cells that can help control and reduce SIV (simian immunodeficiency virus) in animal models. This finding, from Yerkes National Primate Research Center scientists in collaboration with Institut Pasteur, could be key for developing additional treatment options to control HIV/AIDS.

The results were published in Nature Communications.

Antiviral therapy (ART) is the current leading treatment for HIV/AIDS, and is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.

To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates natural killer (NK) cells with impaired functionality. In contrast, natural primate hosts of SIV do not progress to AIDS-like disease. Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.

The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN-alpha to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissues.  

“Our results indicate ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD, a senior research specialist and manager of the Paiardini research lab. “These robust NK cell responses helped clear cells in the lymph nodes, which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV.”

HIV treatment has historically focused on the role of T cells in immunity, so harnessing NK cells opens up different avenues.

Mirko Paiardini, PhD

“This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activities can contribute to controlling the virus,” says Mirko Paiardini, PhD, an associate professor of pathology and laboratory Medicine at Emory University and a researcher at Yerkes. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world.”

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More evidence for autoantibodies in severe COVID-19

A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.

Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.

Last year, immunologist Ignacio Sanz’s lab at Emory demonstrated that patients with severe COVID-19 display signs of immune dysregulation similar to those seen in lupus. A follow-up preprint found the suspected autoantibodies, and several other labs have observed autoantibodies in COVID-19 that may be sabotaging antiviral responses or perturbing blood clotting. Now, an active topic of investigation is whether the autoantibodies last longer or don’t diminish as quickly in long COVID. Stay tuned.

This image has an empty alt attribute; its file name is MaierC.jpg
Cheryl Maier, MD, PhD

However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.

“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”

Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigating blood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.

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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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