Each day, you inhale hundreds of microscopic spores of the fungus Aspergillus fumigatus. For most people, it’s no big deal because their healthy immune system destroys them before they can do any harm.
But for people who take immunosuppressive drugs to prevent organ rejection after a transplant or to treat autoimmune diseases like Crohn’s disease, breathing in the spores can lead to life-threatening infections.
“They are at risk of opportunistic infections by microbes in the environment that normally don’t make people sick because a healthy immune system fights them off,” said Clemson University’s Emily Rosowski, an assistant professor in the College of Science’s Department of Biological Sciences. “But when immunosuppressants depress your immune system, you are susceptible to these opportunistic pathogens.”
Around 30% of immunosuppressed people who get Aspergillosis, the disease caused by the usually harmless Aspergillus fumigatus, die from it. The solution to this potentially fatal problem may lie in reconsidering how immunosuppressant drugs work.
“We need better ways to target more specific immune pathways rather than have these broad immunosuppressive drugs that suppress the whole immune system,” she said.
Rosowski has received a nearly $1.2 million National Institutes of Health MIRA (Maximizing Investigators’ Research Award) grant for her research to better understand which immune pathways downstream of these broadly acting immunosuppressive drugs are important to help control Aspergillus fumigatus infection. MIRAs fund investigators and their general research ideas instead of a narrow set of specific research aims. They also provide robust funding spread over five years, giving scientists more ability to pursue projects or directional changes that arise during the course of their research.
Rosowski’s study targets innate immunity, the body’s natural frontline defense system not specific to any single pathogen. Innate immune responses involve both macrophages and neutrophils. Macrophages are white blood cells that live in all tissues and act as sentinels to recognize and provide the first line of defense against potential pathogens. Neutrophils are short-lived white blood cells that live in the bloodstream and travel to the site of an infection, where they ingest pathogens.
Using larval zebrafish infected by Aspergillus fumigatus, Rosowski’s lab uses tools such as microscopy to understand how immune cells respond to the fungus. Larval zebrafish are used because they have similar genomes and immune responses as humans. In addition, larval zebrafish don’t have any pigment on their skin and are transparent, allowing researchers to see what’s happening inside of the animal as immune cells respond to and clear pathogens.
Nuclear factor kappa B, a protein that regulates the innate immune system, is one of the major pathways inhibited by corticosteroids, a commonly used and broadly acting immunosuppressant. Each type of immune cell — from macrophages and neutrophils to T-cells and B-cells — uses NF kappa B to activate responses to infections.
“Exactly what the outputs of that pathway activation in different cells and which of those outputs are important, for example, to prevent organ rejection versus to treat Crohn’s disease versus to help control infection to Aspergillus, are unknown,” Rosowski said. “So, we want to understand what outputs of those pathways are important for different conditions that require immune activation.”
Knowing that could allow patients to be treated for Crohn’s disease without making them susceptible to other fungal pathogens.
Future research will study the role of these genes and pathways in contexts such as autoimmune diseases.
Fungal pathogens are causing more health issues because of increasing numbers of people taking immunosuppressive drugs. Three classes of antifungal medications are available for patients, none of which are particularly effective.
“Understanding which immune responses are most important to fight these infections will allow us to find treatments that will stimulate or boost immune responses to help control the infection versus only these antifungals that directly target the fungus,” she said.
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