Are immune-experienced mice better for sepsis research?

The goal is to make mouse immune systems and microbiomes more complex and more like those in humans, so the mice they can better model the deadly derangement of Read more

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 Read more

Antibody diversity mutations come from a vast genetic library

The antibody-honing process of somatic hypermutation is not Read more

Immunology

Are immune-experienced mice better for sepsis research?

Why isn’t a laboratory mouse more like a human? There are several answers, beyond the differences in size and physiology between mice and humans, such as microbiome and immunological experience. Emory researchers led by Mandy Ford and Craig Coopersmith recently published a couple papers that aim to take those factors into account.

The goal is to make mouse immune systems and microbiomes more complex and more like those in humans, so the mice they can better model the deadly derangement of sepsis. So far, sepsis research in mice has been a poor predictor of clinical success. This aligns with work at the National Institutes of Health on “wildling” mice, which have microbes more like wild mice. (Lab Land likes noticing a trend that Emory researchers are part of.)

One Emory paper, in FASEB Journal, shows that mortality in a mouse model of sepsis varies according to the commercial facility where the mice came from. When the mice were allowed to live together and exchange microbes, mortality numbers evened out.

Another, published in JCI Insight, looks at mice that have more memory T cells than naïve mice, since adult humans have a high proportion of memory T cells in their immune systems. Other scientists have shown that sepsis leads to a wipeout of memory T cells, and probably vulnerability in defending against infection. 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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Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

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Emory Microbiome Research Center inaugural symposium

Interest in bacteria and other creatures living on and inside us keeps climbing. On August 15 and 16, scientists from a wide array of disciplines will gather for the Emory Microbiome Research Center inaugural symposium.

On the first day, Lab Land is looking forward to hearing from several of the speakers, touching on topics stretching from insects/agricultural pathogens to neurodegenerative disease. The second day is a hands on workshop organized by instructor Anna Knight on sorting through microbiome data. The symposium will be at WHSCAB (Woodruff Health Sciences Center Auditorium). Registration before August 2 is encouraged!

Many of the projects that we highlighted four years ago, when Emory held its first microbiome symposium, have continued and gathered momentum. Guest keynotes are from Rodney Newberry from WUSTL and Gary Wu from Penn.

 

Read more

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B cells off the rails early in lupus

New research on the autoimmune disease systemic lupus erythematosus (SLE) provides hints to the origins of the puzzling disorder. The results are published in Nature Immunology.

In people with SLE, their B cells – part of the immune system – are abnormally activated. That makes them produce antibodies that react against their own tissues, causing a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems.

Scientists at Emory University School of Medicine could discern that in people with SLE, signals driving expansion and activation are present at an earlier stage of B cell differentiation than previously appreciated. They identified patterns of gene activity that could be used as biomarkers for disease development.

Activation can be observed at an early stage of B cell differentiation: resting naive cells (pink ellipse). Adapted from Jenks et al Immunity (2018).

“Our data indicate a disease signature across all cell subsets, and importantly on mature resting B cells, suggesting that such cells may have been exposed to disease-inducing signals,” the authors write.

The paper reflects a collaboration between the laboratories of Jeremy Boss, PhD, chairman of microbiology and immunology, and Ignacio (Iñaki) Sanz, MD, head of the division of rheumatology in the Department of Medicine. Sanz, recipient of the 2019 Lupus Insight Prize from the Lupus Research Alliance, is director of the Lowance Center for Human Immunology and a Georgia Research Alliance Eminent Scholar. The first author is Christopher Scharer, PhD, assistant professor of microbiology and immunology.

The researchers studied blood samples from 9 African American women with SLE and 12 healthy controls. They first sorted the B cells into subsets, and then looked at the DNA in the women’s B cells, analyzing the patterns of gene activity. Sanz’s team had previously observed that people with SLE have an expansion of “activated naïve” and DN2 B cells, especially during flares, periods when their symptoms are worse. Read more

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I3 Venture awards info

Emory is full of fledgling biomedical proto-companies. Some of them are actual corporations with employees, while others are ideas that need a push to get them to that point. Along with the companies highlighted by the Emory Biotech Consulting Club, Dean Sukhatme’s recent announcement of five I3 Venture research awards gives more examples of early stage research projects with commercial potential.

This is the third round of the I3 awards; the first two were Wow! (basic discovery) and Synergy II/Nexus (promoting interdisciplinary collaboration). For the five Venture awards, the Dean’s office is providing a total of $100,000. The companies will then use the momentum to seek larger amounts of funding from various sources. Lab Land is still collecting information on the projects:

 

Faculty Name Technology Relevant links
Ray Dingledine + Thota Ganesh Pyrefin EP2 receptor antagonists vs epilepsy, pain, inflammation New class of potential drugs inhibits inflammation in brain
Mark Goodman, W. Robert Taylor Microbial Medical PET imaging agent for detection of bacterial infections Spoonful of sugar helps infection detection
Carlos Moreno + Christian Larsen ResonanceDx Miniaturized rapid creatinine test for point of care use  
Edmund Waller + Taofeek Owonikoko Cambium Oncology Enhancing responsiveness of pancreatic cancer to immunotherapy The Company’s lead compound was effective in animal studies for pancreatic cancer, melanoma, leukemia and lymphoma.
Chunhui Xu TK High-throughput screening for antiarrhythmic drugs using cardiomyocytes Fetal alcohol toxicity – in a dish // Cardiac ‘disease in a dish’ models advance arrhythmia research
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Repurposing a transplant drug for bone growth

The transplant immunosuppressant drug FK506, also known as tacrolimus or Prograf, can stimulate bone formation in both cell culture and animal models. This info comes from orthopedics researcher Nick Willett, PhD and colleagues, published in International Journal of Molecular Sciences (open access).

Nick Willett, PhD

The results suggest that FK506 might be repurposed as a “stand-alone” replacement for recombinant BMP-2 (bone morphogenic protein 2). That product has been a huge commercial success for Medtronic, in the context of spinal fusion surgeries, although controversial because of cost and side effects.

BMP-2 is more potent gram for gram, but FK506 still may offer some opportunities in local delivery. From Sangadala et al (2019)

One of Willett’s co-authors is orthopedics chair Scott Boden, MD, whose lab previously developed a system to search for drugs that could enhance BMP-2. Previously, other researchers had observed that FK506 can enhance the action of BMP-2 – this makes sense because FK506’s target protein is a regulator of the BMP pathway. Willett’s team used FK506 on its own, delivered in a collagen sponge.

“That is the big finding here, that it has the potential to be used on its own without any BMP-2,” he says.

The sponge is a possible mechanism for getting the drug to tissues without having too many systemic effects. Willett’s lab is now working on refining delivery, dosing and toxicity, he says.

Willett, based at the Atlanta VA Medical Center, is in the Department of Orthopedics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. He and Sree Sangadala, PhD (first author of the IJMS paper) currently have a grant from National Center for Advancing Translational Sciences on this project.

 

 

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Sifting through signs of inflammation to analyze causes of Crohn’s disease

When studying Crohn’s disease – an inflammatory disorder of the gastrointestinal tract, a challenge is separating out potential causes from the flood of systemic inflammation inherent in the condition. Researchers led by Subra Kugathasan, MD recently published an analysis that digs under signs of inflammation, in an effort to assess possible causes.

Graduate student Hari Somineni, in Kugathasan’s lab, teamed up with Emory and Georgia Tech geneticists for a sophisticated approach that may have found some gold nuggets in the inflammatory gravel. The results were published in the journal Gastroenterology.

In studying Crohn’s disease, Emory + Georgia Tech researchers may have found some gold nuggets in the inflammatory gravel.

The group looked at DNA methylation in blood samples from pediatric patients with Crohn’s disease, both at diagnosis and after treatment and follow-up. The information came from blood samples from 164 children with Crohn’s disease and 74 controls, as part of the RISK study, which is supported by the Crohn’s & Colitis Foundation and Kugathasan leads.

DNA methylation is a dynamic process that can influence molecular phenotypes of complex diseases by turning the gene(s) on or off. The researchers observed that disrupted methylation patterns at the time of diagnosis in pediatric Crohn’s disease patients returned to those resembling controls following treatment of inflammation

“Our study emphasized how important it is to do longitudinal profiling – to look at the patients before and after treatment, rather than just taking a cross section,” Somineni says.

Read more

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Sensitive to (transplant) rejection

An experimental screening method, developed by Emory and Georgia Tech scientists, aims to detect immune rejection of a transplanted organ earlier and without a biopsy needle.

The technology is based on nanoparticles that detect granzyme B enzymes produced by killer T cells. When the T cells are active, they slice up the nanoparticles, generating a fluorescent signal that is detectable in urine. The results from a mouse skin graft model were published in Nature Biomedical Engineering, from Gabe Kwong’s lab at GT and Andrew Adams’ at Emory. More extensive story here.

Co-first authors Quoc Mac and Dave Mathews

Adams is also developing technologies for imaging transplant rejection via immunoPET, with Georgia Tech’s Phil Santangelo.

 

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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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