Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

Rabindra Tirouvanziam

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus.

Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the bacteria?

The answer is neutrophils, one of the most abundant types of immune cells and foot soldiers against bacterial infections. When neutrophils get into the lungs in people with CF, they change behavior and shut off the expression of genes that would be important for them to combat bacteria. They stay around in the lungs, and release harmful proteins that interfere with other cells’ ability to clean up the bacteria.

Tirouvanziam’s lab has developed a culture system for studying neutrophil behavior, a model for how they act in the lungs. The system makes the neutrophils pass through a layer of lung epithelial cells. Under the influence of lung fluids obtained from CF patients, neutrophils turn what Tirouvanziam calls GRIM (Granule Release, Immunomodulatory, Metabolic). They’re feeding but not fighting: highly metabolically active, but not producing the molecules needed for bactericidal activity.

In a recent paper published in Cell Reports Medicine, researchers show that they can reverse the GRIM fate by applying alpha-amanitin, which blocks RNA transcription, and bring back bactericidal activity. This is a sledgehammer approach, because alpha-amanitin shuts down everything – it’s the toxic ingredient in destroying angel/death cap mushrooms.

Thus, alpha-amanitin would not be appropriate as a therapeutic medication. But it is a tantalizing hint of more specific approaches to come – related papers are on the way, Tirovanziam says. Reviving the anti-bacterial ability of neutrophils should be applicable regardless of the pathogen, and independent of antibiotic resistance, he adds.

“We can steer them in the right direction,” he says. “We are starting to realize that neutrophils have multiple programs and pathways – sort of like T cells. And we can show that it is being exposed to CF lung fluid that makes them go wrong – it’s not intrinsic to the neutrophils.”

The paper also says that scientists in his lab have been separating lung fluids from CF patients into fractions, in order to isolate the molecular entities responsible for steering neutrophils down the wrong path.

The first author of the Cell Reports Medicine paper was former graduate student Camila Margaroli, currently a postdoc at UAB. Tirouvanziam’s lab is part of Emory’s Department of Pediatrics and the Emory-Children’s Healthcare Center for Cystic Fibrosis and Airways Disease Research.

Posted on by Quinn Eastman in Immunology Leave a comment

Less mucus, more neutrophils: alternative view of CF

A conventional view of cystic fibrosis (CF) and its effects on the lungs is that it’s all about mucus. The inherited disease leads to an accumulation of mucus in the lungs, which appears to be connected with inflammation, susceptibility to infection and loss of lung capacity.

Immunologist Rabin Tirouvanziam has an alternative view, centered on neutrophils. They are a type of immune cell that is very numerous, yet often overlooked, he says.

Rabindra Tirouvanziam, PhD

A new paper, published in Journal of Leukocyte Biology, substantiates his ideas about cystic fibrosis and harnesses them for future diagnostic and therapeutic advances. Tirouvanziam is an assistant professor of pediatrics at Emory University School of Medicine and Emory Children’s Center. He and his colleagues have developed a system for studying neutrophil behavior in a specialized culture, a model of a cell layer in the lung.

Neutrophils behave differently in the diseased lung environment, compared with when they are in the blood. The culture system makes the neutrophils pass through a layer of lung cells, under the influence of lung fluids obtained from CF patients. The culture system opens up the opportunity of testing fluids from patients to mark disease progression, as well as drug discovery: looking for compounds that could deprogram the neutrophils. Read more

Posted on by Quinn Eastman in Immunology Leave a comment