Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

Weakened antibody responses to COVID-19 mRNA vaccines among most patients with multiple Read more

Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype. Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients. Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple Read more

Promiscuous protein droplets regulate immune gene activity

Biochemists at Emory are achieving insights into how an important regulator of the immune system switches its function, based on its orientation and local environment. New research demonstrates that the glucocorticoid receptor (or GR) forms droplets or “condensates” that change form, depending on its available partners. The inside of a cell is like a crowded nightclub or party, with enzymes and other proteins searching out prospective partners. The GR is particularly well-connected and promiscuous, and Read more

neutrophils

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

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Low doses of imatinib can stimulate innate immunity

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.

The results were published this week in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.

Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.

Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment