2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to Read more

EHR data superior for studying sepsis

Analysis of EHR data says sepsis rates and mortality have been holding steady, contrary to what is suggested by after-the-fact Read more

New pediatric digestive/liver disease gene identified by international team

A multinational team of researchers describes a newly identified cause of congenital diarrhea and liver disease in Read more

Immunology

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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Providing the potent part of probiotics

A Emory News item on a helpful part of the microbiome focuses on how the same type of bacteria – lactobacilli – activates the same ancient signaling pathway in intestinal cells in both insects and mammals. It continues a line of research from Rheinallt Jones and Andrew Neish on how beneficial bacteria stimulate wound healing by activating ROS (reactive oxygen species).

Asma Nusrat, MD

A idea behind this research is: if we know what parts of the bacteria stimulate healing, perhaps doctors can deliver that material, or something very close, to patients directly to treat intestinal diseases such as Crohn’s or ulcerative colitis.

This idea has advanced experimentally, as demonstrated by two papers from Jones and Neish’s frequent collaborator, Asma Nusrat, who recently moved from Emory to the University of Michigan. This team had shown that a protein produced by human intestinal cells called annexin A1 activates ROS, acting through the same N-formyl peptide receptors that bacteria do.

Nusrat told me Friday her team began investigating annexins a decade ago at Emory, and it was fortuitous that Neish was working on beneficial bacteria right down the hall, since it is now apparent that annexin A1 and the bacteria are activating the same molecular signals. (Did you know there is an entire conference devoted to annexins? I didn’t until a few days ago.)

In a second Journal of Clinical Investigation paper published this February, Nusrat and her colleagues show that intestinal cells release vesicles containing annexin A1 following injury. The wound closure-promoting effects of these vesicles can be mimicked with nanoparticles containing annexin A1. The nanoparticles incorporate a form of collagen, which targets them to injured intestinal tissue. Read more

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HIV vaccine news: a glass half full

This week, researchers from Yerkes and Emory Vaccine Center led by Cindy Derdeyn published a paper that I first thought was disturbing. It describes how monkeys vaccinated against HIV’s relative SIV (simian immunodeficiency virus) still become infected when challenged with the virus. Moreover, it’s not clear whether the vaccine-induced antibodies are exerting any selective pressure on the virus that gets through.

But then I realized that this might be an example of “burying the lead,” since we haven’t made a big hoopla about the underlying vaccine studies, conducted by Rama Amara. Some of these studies showed that a majority of monkeys can be protected from repeated viral challenge. The more effective vaccine regimens include adjuvants such as the immune-stimulating molecules GM-CSF or CD40L (links are the papers on the protective effects). Read more

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CMV reactivation warps immune system after HSCT

As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.

Leslie Kean, MD, PhD

The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.

CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.

The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more

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Following lupus troublemaker cells, via DNA barcodes

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.

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Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.

Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?

Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.” It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.

The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.

When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.

“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,” Tipton says.

To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters). Read more

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Subset of plasma cells display immune ‘historical record’

You may have read about recent research, published in Science, describing a technique for revealing which viruses have infected someone by scanning antiviral antibodies in the blood.

Emory immunologists have identified corresponding cells in which long-lived antibody production resides. A subset of plasma cells keep a catalog of how an adult’s immune system responded to infections decades ago, in childhood encounters with measles or mumps viruses.

The results, published Tuesday, July 14 in Immunity, could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

“If you’re developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen,” says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare’s Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Lee says that her team’s research on plasma cells in humans provided insights unavailable from mice, since mice don’t live as long and their plasma cells also have a different pattern of protein markers. More here.

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Microbiome enthusiasm at Emory

At what point did the human microbiome become such a hot topic?

When it was shown that babies born by Cesarean section are colonized with different bacteria than those born vaginally? With the cardiovascular studies of microbial byproducts of meat digestion? With the advent of fecal transplant as a proposed treatment for Clostricium difficile infection?

The bacteria and other microbes that live within the human body are thought to influence not only digestive health, but metabolic and autoimmune diseases as well, possibly even psychiatric and neurodevelopmental disorders. The field is being propelled by next-generation sequencing technology, and Nature had to publish an editorial guarding against hype (a major theme: correlation is not causation).

At Emory, investigators from several departments are involved in microbiome-related work, and the number is expanding, and assembling a comprehensive list is becoming more difficult. Researchers interested in the topic are planning Emory’s first microbiome symposium in November, organized by Jennifer Mulle (read her intriguing review on autism spectrum disorders and the microbiome).

Microbial genomics expert Tim Read, infectious diseases specialist Colleen Kraft and intestinal pathologist Andrew Neish have formed an Emory microbiome interest group with a listserv and seminars.

Microbiome symposium sponsors: ACTSI, Hercules Exposome Center, Emory University School of Medicine, Omega Biotek, CFDE, Ubiome. Read more

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Pre-hospital recognition of severe sepsis

 

Severe sepsis, a consequence of the body’s response to infection, is a major cause of death in hospitals. The earlier that doctors recognize that a patient has sepsis, the earlier the patient can be treated with antibiotics, fluids and other measures, and the better the chance of survival.

That’s why critical care and emergency medicine researchers have been looking for ways to spot whether someone coming to the hospital might have sepsis, even before arrival.

At Emory, Carmen Polito, Jonathan Sevransky and colleagues recently published a paper in the American Journal of Emergency Medicine on an emergency medical services screening tool for severe sepsis. Polito and Sevransky are in the division of pulmonary, allergy, critical care and sleep medicine in the Department of Medicine. The tool was evaluated based on Grady emergency medical services data from 2011 and 2012.

“Sepsis is largely a face without a name in the EMS setting, “ Polito says. “The goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.”

Read more

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Why checkpoint inhibitors fall short for some types of cancer

The big news from the recent American Society of Clinical Oncology meeting has been largely about immunotherapy drugs, also known as checkpoint inhibitors. These drugs have been shown to be effective in prolonging life in patients with some types of cancer, such as lung cancer and melanoma, but not others, such as colorectal and prostate cancer.

Lab Land asked oncologist Bradley Carthon and immunology researcher Haydn Kissick why. Both Carthon’s clinical work and Kissick’s lab research on prostate cancer are featured in the new issue of Winship magazine, but the prostate feature just touches on checkpoint inhibitors briefly.

Carthon says the reason checkpoint inhibitors haven’t moved the needle with prostate cancer is “likely due to the absence of infiltration of the prostatic tissue by tumor-associated lymphocytes.”

Checkpoint inhibitors are supposed to unleash the immune system, but if the immune cells aren’t in contact with the cancer cells so that the drugs can spur them into action, they won’t help much. Carthon says: “The answer may be to ‘prime’ the prostate with an agent, then introduce the checkpoint inhibitors.” Read more

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Why HIV’s cloak has a long tail

Virologists at Emory, Yerkes and Children’s Healthcare of Atlanta have uncovered a critical detail explaining how HIV assembles its infectious yet stealthy clothing.

Paul Spearman, MD

For HIV to spread from cell to cell, the viral envelope protein needs to become incorporated into viral particles as they emerge from an infected cell. Researchers led by Paul Spearman have found that a small section of the envelope protein, located on its “tail”, is necessary for the protein to be sorted into viral particles.

The results were published June 1 in Proceedings of the National Academy of Sciences. Read more

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