To explain cancer biology, use metaphors

An expert on doctor-patient communication says: let the explanatory metaphors Read more

Enhanced verbal abilities in the congenitally blind

Congenitally blind study participants displayed superior verbal, but not spatial abilities. Possibly reflects their greater reliance on verbal information, and the recruitment of the visual cortex for verbal Read more

Three remarkable Emory case reports from #ACC17

Three remarkable case reports being presented at the American College of Cardiology meeting, including cardiac electrical storm, reverse Takotsubo and congenital heart Read more

Emory Vaccine Center

Zika immunology from returned travelers

At the American Association for the Advancement of Science meeting in Boston last weekend, Emory Vaccine Center researcher Mark Mulligan presented some limited findings on immune responses in Zika-infected humans, who were returned US travelers or expatriates.

The results were intriguing, despite the small number of study participants: five, two of whom were pregnant. Detailed information has not been available about immune responses against Zika in humans, especially T cell responses.

Highlights from Mulligan’s abstract:

*All five seemed to have a hole in their immune systems – functional antiviral “killer” CD8 T cells were rare, despite activation of CD8 T cells in general and strong responses from other cell types.

*Cross-reactive immune responses, based on previous exposure to dengue and/or yellow fever vaccine, may have blunted Zika’s peak.

*”Even with prolonged maternal viremia, both pregnancies resulted in live births of apparently healthy babies.” Read more

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Zika virus blindfolds immune alarm cells

Important immune alarm cells — dendritic cells — are fighting Zika virus with an arm tied behind their backs, scientists from Emory Vaccine Center report.

Dendritic cells are “sentinel” cells that alert the rest of the immune system when they detect viral infection. When Zika virus infects them, it shuts down interferon signaling, one route for mustering the antiviral troops. However, another antiviral pathway called RIG-I-like receptor (RLR) signaling is left intact and could be a target for immunity-boosting therapies, the researchers say.

Mehul Suthar, PhD in the lab with graduate students Kendra Quicke and James Bowen

The findings were published on Feb. 2 in PLOS Pathogens.

Zika was known to disrupt interferon signaling, but Emory researchers have observed that it does so in ways that are distinct from other related flaviviruses, such as Dengue virus and West Nile virus. The findings give additional insight into how Zika virus is able to counter human immune defenses. Read more

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Access to HIV’s hideouts: T cells that take on their own

Police procedural television shows, such as Law + Order, have introduced many to the Internal Affairs Bureau: police officers that investigate other police officers. This group of unloved cops comes to mind in connection with the HIV/AIDS research published this week by Rama Amara’s lab at Yerkes National Primate Research Center and Emory Vaccine Center.

“Killer” antiviral T cells (red spots) can be found in germinal centers. The green areas are B cell follicles, which HIV researchers have identified as major reservoirs for the virus. Image courtesy of Rama Amara.

HIV infection is hard to get rid of for many reasons, but one is that the virus infects the cells in the immune system that act like police officers. The “helper” CD4 T cells that usually support immune responses become infected themselves. For the immune system to fight HIV effectively, the “killer” CD8 antiviral T cells would need to take on their own CD4 colleagues.

When someone is HIV-positive and is taking antiretroviral drugs, the virus is mostly suppressed but sticks around in a reservoir of inactive infected cells. Those cells hide out in germinal centers, specialized areas of lymph nodes, which most killer antiviral T cells don’t have access to. A 2015 Nature Medicine paper describes B cell follicles, which are part of germinal centers, as “sanctuaries” for persistent viral replication. (Imagine some elite police unit that has become corrupt, and uniformed cops can’t get into the places where the elite ones hang out. The analogy may be imperfect, but might help us visualize these cells.)

Amara’s lab has identified a group of antiviral T cells that do have the access code to germinal centers, a molecule called CXCR5. Knowing how to induce antiviral T cells displaying CXCR5 will be important for designing better therapeutic vaccines, as well as efforts to suppress HIV long-term, Amara says. The paper was published in PNAS this week. Read more

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Antiviral success makes some immune cells stickier

As they succeed in clearing a viral infection from the body, some virus-hunting T cells begin to stick better to their target cells, researchers from Emory Vaccine Center and Georgia Tech have discovered.

The increased affinity helps the T cells kill their target cells more efficiently, but it depends both on the immune cells’ anatomic location and the phase of the infection.

The results were published this week in the journal Immunity.

Arash Grakoui, PhD

Arash Grakoui, PhD

After the peak of the infection, cells within the red pulp of the spleen or in the blood displayed a higher affinity for their targets than those within the white pulp. However, the white pulp T cells were more likely to become long-lasting memory T cells, critical for vaccines.

“These results provide a better understanding of how memory precursor populations are established and may have important implications for the development of efficacious vaccines,” the scientists write.

In the mouse model the researchers were using, the differences in affinity were only detectable a few days after the non-lethal LCMV viral infection peaks. How the differences were detected illustrates the role of serendipity in science, says senior author Arash Grakoui, PhD.

Typically, the scientists would have taken samples only at the peak (day 7 of the infection) and weeks later, when memory T cells had developed, Grakoui says. In January 2014, the weather intervened during one of these experiments. Snow disrupted transportation in the Atlanta area and prevented postdoctoral fellow Young-Jin Seo, PhD from taking samples from the infected mice until day 11, which is when the differences in affinity were apparent.

Seo and Grakoui collaborated with graduate student Prithiviraj Jothikumar and Cheng Zhu, PhD at Georgia Tech, using a technique Zhu’s laboratory has developed to measure the interactions between T cells and their target cells. Co-author Mehul Suthar, PhD performed gene expression analysis.

Read more

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Dengue infection makes exhausted T cells?

An ongoing collaboration between the Emory Vaccine Center and the ICGEB (International Centre for Genetic Engineering and Biotechnology) in New Delh, investigating immune responses to dengue virus, is getting some attention.

A Journal of Virology paper published by the collaboration was highlighted by Nature Asia. In that paper, the researchers show that in dengue infection, the group of antiviral immune cells known as CD8+ T cells undergoes a massive expansion. That could be dangerous if all of the CD8 T cells were making inflammatory cytokines, but they do not. Only a small fraction are making cytokines.

The authors point out that this phenomenon is “somewhat reminiscent of T-cell exhaustion seen under the conditions of prolonged antigenic stimulus in chronic viral infections [which has been studied in detail by Rafi Ahmed and colleagues] or closely resembles the ‘stunned’ phenotype reported in febrile phase of other acute infections such as HIV and viral hepatitis… The IFN-γ unresponsiveness acquired during the massive antigen-driven clonal expansion is likely to ensure that these cells do not cause excessive inflammation at the time that their numbers are high during the febrile phase of dengue disease.” Read more

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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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The cure word, as applied to HIV

HIV researchers are becoming increasingly bold about using the “cure” word in reference to HIV/AIDS, even though nobody has been cured besides the “Berlin patient,” Timothy Brown, who had a fortuitous combination of hematopoetic stem cell transplant from a genetically HIV-resistant donor. Sometimes researchers use the term “functional cure,” meaning under control without drugs, to be distinct from “sterilizing cure” or “eradication,” meaning the virus is gone from the body. A substantial obstacle is that HIV integrates into the DNA of some white blood cells.

HIV cure research is part of the $35.6 million, five-year grant recently awarded by the National Institutes of Health to Yerkes/Emory Vaccine Center/Emory Center for AIDS Research. Using the “shock and kill” approach during antiviral drug therapy, researchers will force HIV (or its stand-in in non-human primate research, SIV) to come out of hiding from its reservoirs in the body. The team plans to test novel “latency reversing agents” and then combine the best one with immunotherapeutic drugs, such as PD-1 blockers, and therapeutic vaccines.

The NIH also recently announced a cluster of six HIV cure-oriented grants, named for activist Martin Delaney, to teams led from George Washington University, University of California, San Francisco, Fred Hutchinson Cancer Research Center, Wistar Institute, Philadelphia, Beth Israel Deaconess Medical Center and University of North Carolina. Skimming through the other teams’ research plans, it’s interesting to see the varying degrees of emphasis on “shock and kill”/HIV latency, enhancing the immune response, hematopoetic stem cell transplant/adoptive transfer and gene editing weaponry vs HIV itself.

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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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Fooling the test: antibiotic resistant bacteria that look susceptible

A diagnostic test used by hospitals says a recently isolated strain of bacteria is susceptible to the “last resort” antibiotic colistin. But the strain actually ignores treatment with colistin, causing lethal infections in animals.

Through heteroresistance, a genetically identical subpopulation of antibiotic-resistant bacteria can lurk within a crowd of antibiotic-susceptible bacteria. The phenomenon could be causing unexplained treatment failures in the clinic and highlights the need for more sensitive diagnostic tests, researchers say.

In Nature Microbiology (published online Monday, May 9), scientists led by David Weiss, PhD, describe colistin-heteroresistant strains of Enterobacter cloacae, a type of bacteria that has been causing an increasing number of infections in hospitals around the world.

“Heteroresistance has been observed previously and its clinical relevance debated,” Weiss says. “We were able to show that it makes a difference in an animal model of infection, and is likely to contribute to antibiotic treatment failures in humans.”

Weiss is director of the Emory Antibiotic Resistance Center and associate professor of medicine (infectious diseases) at Emory University School of Medicine and Emory Vaccine Center. His laboratory is based at Yerkes National Primate Research Center. The co-first authors of the paper are graduate students Victor Band and Emily Crispell.

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Malaria vaccine development: chimeric protein, no myth

Third in a series on malaria immunology from graduate student Taryn McLaughlin. Sorry for the delay last week, caused by technical blog glitches.

It’s easy for me to find reasons to brag when it comes to research here at Emory. However, even an unbiased person should be excited about the malaria vaccine platform being developed by Alberto Moreno at the Emory Vaccine Center.

His vaccine is based on a chimeric protein (a protein that is a combination of bits and pieces of multiple proteins, a la the creature from Greek mythology) that should get your immune system to target multiple stages of the Plasmodium vivax life cycle. Part of it targets the infectious sporozoite, part of it targets the blood stage merozoite, and part of it will even target the transmitted gamete in future versions. This seems like a no brainer. Of course we should be targeting multiple stages! 
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