Overcoming cardiac pacemaker "source-sink mismatch"

Instead of complication-prone electronic cardiac pacemakers, biomedical engineers at Georgia Tech and Emory envision the creation of “biological Read more

Hope Clinic part of push to optimize HIV vaccine components

Ten years ago, the results of the RV144 trial– conducted in Thailand with the help of the US Army -- re-energized the HIV vaccine field, which had been down in the Read more

Invasive cancer cells marked by distinctive mutations

What does it take to be a leader – of cancer cells? Adam Marcus and colleagues at Winship Cancer Institute are back, with an analysis of mutations that drive metastatic behavior among groups of lung cancer cells. The findings were published this week on the cover of Journal of Cell Science, and suggest pharmacological strategies to intervene against or prevent metastasis. Marcus and former graduate student Jessica Konen previously developed a technique for selectively labeling “leader” Read more

influenza

Immunologists identify T cell homing beacons for lungs

Scientists have identified a pair of molecules critical for T cells, part of the immune system, to travel to and populate the lungs. A potential application could be strengthening vaccines against respiratory pathogens such as influenza.

The findings were published online Thursday, September 26 in Journal of Experimental Medicine.

T cells in the lungs, courtesy of Alex Wein. Blue represents respiratory epithelium (EpCAM), while various T cells stain red, yellow or green.

Much research on immunity to influenza virus focuses on antibodies, infection- or vaccine-induced proteins in the blood that can smother viruses. But CD8 T cells, which survey other cells for signs of viral infection and kill infected cells, are an important arm of our defenses too. The epitopes – or bits of viral protein – they recognize generally do not change from year to year.

Researchers led by Jacob Kohlmeier, PhD, at Emory University School of Medicine wanted to learn more about what’s needed to get CD8 T cells into the lungs, since the lungs will often contain the first cells incoming virus will have a chance to infect. However, T cells don’t stick around in the lungs for extended amounts of time.

“The airways are a unique environment in the body,” says Alex Wein, a MD/PhD student who trained in Kohlmeier’s lab. “They’re high in oxygen but low in nutrients. Unlike other tissues, when T cells enter the airways, it’s a one-way trip and they have a half-life of a few weeks, so they must be continually repopulated.”

Wein, his fellow MD/PhD Sean McMaster, now at Boston Consulting Group, and Shiki Takamura at Kindai University are co-first authors of the paper. Kohlmeier is assistant professor of microbiology and immunology and part of the Emory-UGA Center of Excellence for Influenza Research and Surveillance.

The researchers showed that two molecules, called CXCR6 and CXCL16, are needed for CD8 T cells to reach the airways in mice. CXCR6 is found on T cells and CXCL16 is produced by the epithelial cells lining the airways of the lungs. Read more

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One more gene between us and bird flu

We’re always in favor of stopping a massive viral pandemic, or at least knowing more about what might make one happen. So we read a recent PLOS Pathogens paper with interest. The general theme is similar to this February 2019 paper from Anice Lowen’s lab in PNAS. To paraphrase Bill Murray in Ghostbusters: birds and humans living together, mass hysteria!

Here, Emory researchers looked at the M segment of influenza virus, which appears to determine host restriction, or the ability of viruses that infect bird cells to migrate to mammals. The M segment, was important for emergence of the 2009 H1N1 pandemic flu.

One of eight influenza gene segments, the M segment encodes a protein that can interfere with cellular functions (autophagic vesicles) on which the virus relies. The new data reveal that reductions in M2 protein occurred in connection with past important adaptation events, such as when a Eurasian avian-like swine virus emerged from birds in the 1970s.

“This mechanism constitutes a novel paradigm in RNA virus host adaptation, and reveals a new species barrier for IAV, which may be highly relevant for the emergence of avian IAVs into humans,” the authors conclude. Read more

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Bird flu shuffle probes viral compatibility

When influenza viruses that infect birds and humans meet in the same cell, they can shuffle their genomes and produce new strains that might have pandemic potential. Think of this process, called reassortment, as viruses having sex.

In the last several years, public health officials have been monitoring two varieties of bird flu viruses with alarming properties: H7N9 and H5N8. Scientists at Emory have been probing the factors that limit reassortment between these strains and a well-known strain (H3N2) that has been dominating the last few flu seasons in the United States.

Helen Branswell has an article in STAT this week, explaining that H5N8 actually emerged from reassortment  involving much-feared-but-not-damaging-to-humans-so-far H5N1:

Several years ago, these viruses effectively splintered, with some dumping their N1 neuraminidase — a gene that produces a key protein found on the surface of flu viruses — and replacing it with another. The process is called reassortment, and, in this case, it resulted in the emergence of a lot of new pairings over a fairly short period of time.

The most common and most dangerous viruses to emerge — for birds at least — have been H5N6 and H5N8 viruses. Both are highly pathogenic, meaning they kill domestic poultry.

“The H5N1 virus has not gone away. It’s just changed into different versions of itself,” explained influenza expert Malik Peiris, a professor of virology at the University of Hong Kong.

From the Emory study, the good news is that “packaging signals” on the H5 and H7 viral RNA genomes are often incompatible with the H3N2 viruses. That means it could be difficult for segments of the genome from the bird viruses to get wrapped up with the human viruses. But mix and match still occurred at a low level, particularly with H5N8. Read more

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Four hot projects at Emory in 2017

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

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Flu meeting at Emory next week

We are looking forward to the “Immunology and Evolution of Influenza” symposium next week (Thursday the 25th and Friday the 26th).

The symposium is taking place in Whitehead Auditorium in the Whitehead Biomedical Research Building. Talks from flu researchers based around the country, followed by a poster session, are on Thursday. From Emory, Jacob Kohlmeier and Rafi Ahmed are speaking Friday morning.

Organizers are asking for registration by Friday the 19th. The symposium is jointly sponsored by the Center for Inference and Dynamics of Infectious Diseases, funded by NIGMS, and the Center for Modeling Immunity to Influenza Infection, funded by NIAID.

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How antiviral antibodies become part of immune memory

Weapons production first, research later. During wartime, governments follow these priorities, and so does the immune system.

When fighting a bacterial or viral infection, an otherwise healthy person will make lots of antibodies, blood-borne proteins that grab onto the invaders. The immune system also channels some of its resources into research: storing some antibody-making cells as insurance for a future encounter, and tinkering with the antibodies to improve them.

In humans, scientists know a lot about the cells involved in immediate antibody production, called plasmablasts, but less about the separate group of cells responsible for the “storage/research for the future” functions, called memory B cells. Understanding how to elicit memory B cells, along with plasmablasts, is critical for designing effective vaccines.

EbolaBcells

Activated B cells (blue) and plasmablasts (red) in patients hospitalized for Ebola virus infection, with a healthy donor for comparison. From Ellebedy et al Nature Immunology (2016).

Researchers at Emory Vaccine Center and Stanford’s Department of Pathology have been examining the precursors of memory B cells, called activated B cells, after influenza vaccination and infection and during Ebola virus infection. The Ebola-infected patients were the four who were treated at Emory University Hospital’s Serious Communicable Disease Unit in 2014.

The findings were published Monday, August 15 in Nature Immunology.

“Ebola virus infection represents a situation when the patients’ bodies were encountering something they’ve never seen before,” says lead author Ali Ellebedy, PhD, senior research scientist at Emory Vaccine Center. “In contrast, during both influenza vaccination and infection, the immune system generally is relying on recall.”

Unlike plasmablasts, activated B cells do not secrete antibodies spontaneously, but can do so if stimulated. Each B cell carries different rearrangements in its DNA, corresponding to the specificity and type of antibody it produces. The rearrangements allowed Ellebedy and his colleagues to track the activated B cells, like DNA bar codes, as an immune response progresses. Read more

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A distinguished flu vaccine researcher

Congratulations to Richard Compans, PhD, who delivered the Dean’s Distinguished Faculty Lecture on May 12, joining a select group of Emory researchers who have received this award. After Dean Chris Larsen presented the award, Compans also received a Catalyst award from the Georgia Research Alliance, presented by GRA President and CEO Mike Cassidy.compans115a-2

At Emory, Compans has led research on ways to improve influenza vaccination, such as vaccines based on non-infectious virus-like particles and microneedle patches for delivery (now being tested clinically). The 2009 H1N1 flu epidemic, as well as concern about pandemic avian flu, have meant that Compans’ work has received considerable attention in the last several years. In his talk, he also discussed his early work on the structure of influenza virus, the virus’s complex ecology, and the limitations of current flu vaccines.

Compans was recruited to Emory from UAB in 1992 and was chair of Emory’s microbiology and immunology department for more than a decade. He was also instrumental in recruiting Rafi Ahmed to establish and lead the Emory Vaccine Center. He is now co-principal investigator of the Emory-UGA Center of Excellence for Influenza Research and Surveillance.

Some recent papers that illustrate the extent of Compans’ influence: Read more

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‘Mountain of data’ on flu vaccine responses

Bali Pulendran’s lab at Emory Vaccine Center teamed up with UCSD researchers and recently published a huge analysis of immune responses after seasonal flu vaccination (Immunity is making it available free this week, no subscription needed). Hundreds of volunteers at the Vaccine Center’s Hope Clinic took part in this study.

Note — this study looked at antibody responses to flu vaccines, but didn’t assess protection: whether study participants actually became sick with flu or not.

Our write-up is here. Immunity’s preview, from the Karolinska Institute’s Petter Brodin, is here, Cell Press’s press release is here.

Three points we wanted to call attention to:

*Long-lasting antibodies A surprising finding was how the “molecular signatures” that predict the strength of the immune response a few weeks after vaccination did not predict how long anti-flu antibodies stayed around. Instead, a separate set of signatures predicted the durability of antibody levels.

These distinct signatures may be connected with how plasma cells, responsible for antibody production, need to find homes in the bone marrow. That sounds like the process highlighted by Eun-Hyung Lee and colleagues in an Immunity paper published in July. In bone marrow samples from middle-aged volunteers, her team had found antibody-secreting cells that survive from childhood infections.

*Interfering (?) activation of NK cells/monocytes in elderly While the researchers found people older than 65 tended to have weaker antibody responses to vaccination, there were common elements of molecular signatures that predicted strong antibody responses in younger and older volunteers. However, elderly volunteers tended to have stronger signatures from immune cells that are not directly involved in producing antibodies (monocytes and ‘natural killer’ cells), both at baseline and after vaccination.

From the discussion: “This indicates a potential connection between the baseline state of the immune system in the elderly and reduced responsiveness to vaccination.” Additional comments on this from Shane Crotty in Brad Fikes’ article for the Union Tribune.

*The mountain of data from this and similar studies is available for use by other researchers on the web site ImmPort.

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Progress on universal flu vaccine

Flu viruses are constantly mutating and every year the seasonal flu shot is updated to keep up with the viruses that are making people sick. Readers interested in the prospect of a “universal flu vaccine” may have noticed some experimental progress on that theme this week.

The reports build on findings some years ago from Emory Vaccine Center researchers led by Rafi Ahmed. Ahmed’s team had showed that people infected by the 2009 H1N1 flu strain developed broadly protective antibodies, and separately, so did volunteers immunized against the H5N1 avian flu virus.

Some background: the head region of the flu virus’s mushroom-like hemagglutinin protein is more variable, and more exposed to the immune system, while the stem/stalk region is less variable.

The underlying idea is: if someone’s immune system is exposed to flu viruses different enough than what it has seen before (like in the 2009 H1N1 outbreak and the H5N1 study), the antibodies to the stem region become more important and more prominent.

The NIAID team fused the flu hemagglutinin to ferritin to make nanoparticles

The NIAID team fused the flu hemagglutinin to ferritin, a platform for further protein engineering.

This week, what the researchers from NIAID (Nature Medicine) and Scripps/J&J (Science) showed is that experimental vaccines made from the stem region only can be broadly protective in several animal models. This required some protein engineering and reconstruction because chopping off the head of the hemagglutinin protein makes it fall apart.

Emory Vaccine Center’s Walter Orenstein, in comments for Genetic Experts News Service, wrote:

These are animal studies, so we are some way off for development and testing of a vaccine in humans. The technique is promising and a step in the right direction. Read more

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Oink! — Glycan receptors for flu viruses

Pigs are natural hosts for influenza viruses that can infect humans, in particular the 2009 and, going way back, 1918 H1N1 flu strains. So to understand how influenza infections spread in the body, biochemists and virologists look at pigs.

Biochemistry chair Rick Cummings’ group has a paper in PNAS this week examining the carbohydrates or glycans on the surfaces of pig lung cells, using their “shotgun glycomics” library approach. MMG graduate student Lauren Byrd-Leotis is the first author.Piglung

“The results illustrate the repertoire of specific, endogenous N-glycans of pig lung glycoproteins for virus recognition and offer a new direction for studying endogenous glycan functions in viral pathogenesis,” the team reports.

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