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

Connections between starvation and immunological memory

Researchers at Emory have been revealing several connections between cells’ responses to starvation and immunological memory. The latest example of this is a paper in Nature Immunology from Rafi Ahmed’s lab, showing that the cellular process of autophagy (literally: self-consumption) is essential for forming and maintaining memory T cells.

This finding has some practical implications for vaccination and could point the way to additives that could boost vaccine effectiveness in elderly humans. Researchers at Oxford have demonstrated that autophagy is diminished in T cells from aged mice, and T cell responses could be boosted in older mice using the autophagy-inducing compound spermidine. Read more

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Strategy to defend vs double hit at beginning of life

Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.

Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.

The researchers show that a type of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.

A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.

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Cell death drug discovery: come at the king, you best not miss

It may seem like a stretch to compare an enzyme to a notorious criminal, especially one as distinctive as Omar Little, a character from the HBO drama The Wire played by Michael Kenneth Williams.

But stick with me, I’ll explain.

TheWire-OmarLittle2-Portable

Omar is a stick-up man who robs street-level drug dealers. When drug dealer henchmen Stinkum and Weebay ambush him, they are unsuccessful and Stinkum is killed. Omar tells Weebay, who is hiding behind a car: “Come at the king, you best not miss.”

At Emory, Ed Mocarski, Bill Kaiser and colleagues at GlaxoSmithKline have been studying an enzyme called RIP3. RIP3 is the king of a form of programmed cell death called necroptosis. RIP3 is involved in killing cells as a result of several inflammation-, infection- or injury-related triggers, so inhibitors of RIP3 could be useful in modulating inflammation in many diseases.

In a new Molecular Cell paper, Mocarski, Kaiser and their co-authors lay out what happened when they examined the effects of several compounds that inhibit RIP3 in cell culture. These compounds stopped necroptosis, but unexpectedly, they unleashed apoptosis, another form of programmed cell death.  Read more

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Breaking the rules: flagellin vs rotavirus

Flagellin is a bacterial protein that activates the innate immune system. Its name comes from flagella, the whips many bacteria use to propel themselves.

On Thursday, a team of researchers led by immunologist Andrew Gewirtz reported in Science that treatment with flagellin can prevent or cure rotavirus infection in animals. Rotavirus infection is one of the most common causes of severe diarrhea and is a major cause of death for children in developing countries.

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Andrew Gewirtz, PhD

Gewirtz’s lab is now at Georgia State, but he and his colleagues initiated this research while at Emory and several co-authors are affliliated with Emory, including immunologist Ifor Williams.

These findings are remarkable for several reasons. One is: give the immune system something from bacteria, and it’s better at fighting a virus? As Gewirtz says in a GSU news release: “It’s analogous to equipping an NFL defense with baseball bats. Blatant violation of all the rules but yet, at least in this case, very effective.”

For me, what was most surprising about this paper was that treatment with flagellin, or immune signaling proteins activated by flagellin, can get mice with severely impaired immune systems – no T cells or B cells at all — to evict rotavirus. These are mice that have to be reared under special conditions because they are vulnerable to other infections. Interferons, well-known antiviral signaling molecules, are also not involved in resisting or evicting rotavirus infection, the researchers found. Read more

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Paul Offit: rock star of vaccine advocacy

This piece in the Los Angeles Times gives a helpful preview of what Paul Offit’s talk at Emory next week may be like. He also gave a keynote speech at the Association for Health Care Journalists meeting this spring.

Offit is the chief of the Division of Infectious Diseases and the Director of the Vaccine Education Center at the Children’s Hospital of Philadelphia. He is speaking at noon at the Health Sciences Research Building Auditorium on Nov. 18.

Offit is also speaking that morning at Childrens’ Scottish Rite hospital on the 1991 measles outbreak in Philadelphia. The emails I’ve been getting for the noon event ask people to register.

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Ebola’s capriciousness in kids

Anita McElroy, a pediatric infectious disease specialist at Emory, and her colleagues at the CDC, led by Christina Spiropoulou, have been getting some attention for their biomarker research on Ebola virus infection. Sheri Fink from the New York Times highlighted their work in a Nov. 9 report on the infection’s capriciousness. Genetics may also play a role in surviving Ebola infection, as recent animal research has suggested.

McElroy’s team’s findings attracted notice because their results suggest that Ebola virus disease may affect children differently and thus, children may benefit from different treatment regimens than those for adults. The authors write that early intervention to prevent injury to the lining of blood vessels — using statins, possibly — might be a therapeutic strategy in pediatric patients. Read more

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No junk: long RNA mimics DNA, restrains hormone responses

It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.

Unlike many genes scientists are familiar with, Gas5 does not encode a protein. It gets transcribed into RNA, like many other genes, but with Gas5 the RNA is what’s important, not the protein. The RNA accumulates in cells subjected to stress and soaks up steroid hormone receptors, preventing them from binding DNA and turning genes on and off.

Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.

The results were published Friday in Nature Communications.

Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more

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FDA approves treatment for acquired hemophilia

On Oct. 24, the Food and Drug Administration approved Obizur, a treatment for acquired hemophilia A. Obizur was originally developed by a research team led by Emory hematologist Pete Lollar. The Obizur technology was licensed by Emory in 1998 to startup company Octagen (more about Octagen from Philadelphia Business Journal) and eventually brought to commercial availability by the pharmaceutical firm Baxter International.

Lollar is Hemophilia of Georgia Professor of Pediatrics in the Aflac Cancer and Blood Disorders Center at Emory University School of Medicine and Children’s Healthcare of Atlanta. The team that developed the drug included Ernest Parker, John Healey and Rachel Barrow, and followed a research collaboration between Lollar and Emory cardiologist Marschall Runge (now at UNC).

Hemophilia is a group of blood clotting disorders leading to excessive bleeding that can occur spontaneously or following injury or surgery. Hemophilia A is caused by a deficiency of clotting factor VIII, and can be either inherited or acquired.

In acquired hemophilia A, the immune system is somehow provoked into making antibodies against factor VIII that inactivate it. Acquired hemophilia is a challenge for doctors to deal with because patients frequently present with severe, life threatening bleeding and also because it’s a surprise: patients do not have a previous personal or family history of bleeding episodes. Antibodies to factor VIII also can be a problem for approximately 30 percent of patients with inherited hemophilia.

Lollar’s team developed a modified form of factor VIII, derived from the protein sequence of pigs, which is less of a red flag to the immune system. Read more

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Bits from HIV + Aging conference

What conferences like the HIV + Aging meeting recently held by Emory in Decatur offer the visiting writer: anecdotes that illustrate issues of clinical care.

To illustrate her point that assumptions about who is likely to develop a new HIV infection may lead doctors to miss possible diagnoses, keynote speaker Amy Justice from Yale described a patient who was seen last year at Yale-New Haven Hospital.

A 60 year old man reported fatigue and had lost 40 pounds over the course of a year. Despite those symptoms, and the discovery of fungal and viral infections commonly linked to HIV/AIDS, it took nine months before a HIV test was performed on the patient, a delay Justice deplored.

Sex and substance abuse do not end at age 50, she said, citing data showing that the risk of HIV transmission can be greater among older adults, and that substance abuse is more likely among adults who are HIV positive compared to those who are HIV negative.

Justice also highlighted the issue of polypharmacy (interactions between prescription drugs at the same time), a concern even in people who are not living with HIV. Common blood pressure medications taken by older adults to prevent heart disease have been suspected of increasing the risk for falls. That’s a problem especially for people living with HIV, because HIV infection has been linked to weakened bone. Read more

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From Berlin to Yerkes

Yerkes immunologist Guido Silvestri and colleagues have a paper in PLOS Pathogens shedding light on the still singular example of Timothy Brown, aka “the Berlin patient”, the only human cured of HIV. Hat tip to Jon Cohen of Science, who has a great explanatory article.

Recall that Brown had lived with HIV for several years, controlling it with antiretroviral drugs, before developing acute myeloid leukemia. In Berlin, as treatment for the leukemia, he received a bone marrow transplant — and not just from any donor; the donor had a HIV-resistance mutation. What was the critical ingredient that enabled HIV to be purged from his body?

Conditioning: the chemotherapy/radiation treatment that eliminates the recipient’s immune system before transplant? HIV-resistant donor cells? Or graft-vs-host disease: the new immune system attacking the old?

Silvestri and colleagues performed experiments with SHIV-infected non-human primates that duplicate most, but not all, of the elements of Brown’s odyssey. The results demonstrate that conditioning, by itself, does not eliminate the virus from the body. But in one animal, it came close. Frustratingly, that animal’s kidneys failed and researchers had to euthanize it. In two others, the virus came back after transplant.

A critical difference from Brown’s experience is that monkeys received their own virus-free blood-forming stem cells instead of virus-resistant cells. Cohen reports that Silvestri hopes to do future monkey experiments that test more of these variables, including transplanting the animals with viral-resistant blood cells that mimic the ones that Brown received. 

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