Two items relevant to long COVID

One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater. A recent report from the United Kingdom, published in PLOS Medicine, studied more than Read more

All your environmental chemicals belong in the exposome

Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for Read more

Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009. Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful. The researchers think that this signature, Read more

Rabindra Tirouvanziam

Neutrophils flood lungs in severe COVID-19

“First responder” cells called neutrophils are the dominant type of immune cells flooding the airways of people with severe COVID-19, according to a recent analysis of African-American patients in Emory hospitals.

The findings were posted on the preprint server Biorxiv prior to peer review.

Neutrophils are the most abundant immune cells in the blood, and usually the first to arrive at the site of a bacterial or viral infection. But in the lungs of severe COVID-19 patients, neutrophils camp out and release tissue-damaging enzymes, the new research shows. They also produce inflammatory messengers that induce more neutrophils to come to the lungs. 

Lung inflammation photo from NIEHS. Most of these dense small cells are neutrophils

This circulating cell type enters the lung and initiates a self-sustaining hyper-inflammation that leads to acute respiratory distress syndrome (ARDS), the leading cause of mortality in COVID-19, says lead author Eliver Ghosn assistant professor of medicine at Emory University School of Medicine.

“Our findings reveal novel therapeutic targets, and developing tactics to intervene could benefit severe patients in the ICU, particularly those that are most vulnerable,” Ghosn says. “We compared our lung data with matching blood samples for all the patients, and we were able to identify the subtype of neutrophils in the blood that is most likely to infiltrate the lungs of severe patients and cause ARDS.”

Somewhat counter-intuitively, Emory researchers had difficulty detecting SARS-CoV-2 infected cells in the upper airways of hospitalized patients. This result, consistent with findings by others, may explain why antiviral drugs such as remdesivir are ineffective once systemic inflammation has gained momentum; lung injury comes more from the influx of immune cells, such as neutrophils, rather than viral infection itself.

When Ghosn and his colleagues began examining immune cells in COVID-19, they found that almost all of the hospitalized patients they encountered were African-American. This highlights the racial disparities of the COVID-19 pandemic, especially in Georgia, and Ghosn’s team decided to “lean in” and focus on African-Americans. They collaborated closely with Eun-Hyung Lee’s lab at Emory to collect samples from hospitalized patients. 

“We believe these results can have broader implications and be applied to other demographics that suffer from similar lung pathology,” Ghosn says.

Read more

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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