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  • Tracing the migration patterns of neutrophils— the most common white blood cells in the bloodstream—is something of an obsession for the researchers in Jonathan Reichner, PhD’s lab in the Division of Surgical Research at Rhode Island Hospital. These cells are the first responders of the human immune system, called in to fight bacterial and fungal infections.

    Jonathan Reichner, PhD
    Jonathan Reichner, PhD

    Two of the many questions Reichner’s team seeks to answer are: How do neutrophils know how to find the site of infection—a wound in the foot, say, rather than in the shoulder? And how can we safely and effectively boost their healing activity?

    A potential answer to both questions rests with a molecule, beta-glucan (β-glucan), which is naturally occurring in the cell wall of baker’s yeast as well as a variety of fungi and plants. β-glucan is associated with strengthening immune system responses and speeding up the migration rate of neutrophils. It also has anti-tumor properties, which may help cancer patients.

    “The action of β-glucan is unique in that it alters and enhances the process of how cells migrate from the bloodstream to get to a site of injury or infection,” says Reichner, associate professor in the department of surgery in The Warren Alpert Medical School of Brown University and director of the graduate program in pathobiology in Brown’s Division of Biology and Medicine.

    Reichner’s team has discovered that a receptor on the surface of neutrophils, known as the CR3 integrin, binds to β-glucan. This binding begins a cellular reaction that activates cells to migrate more rapidly towards the source of an infection and to destroy pathogens more effectively. β-glucan binding to the CR3 integrin may also induce neutrophils to kill cancer when partnered with other therapies such as anti-cancer antibodies.

    “When β-glucan binds to the CR3 integrin, the integrin itself undergoes fascinating structural changes,” says Reichner. “On normal neutrophils, the integrin is folded into a compact, inactive state. When disease is present, the integrin unfolds into an upright posture and the neutrophil is in its most highly active state. The problem is that highly active neutrophils can cause collateral tissue damage while destroying pathogens.”

    Neutrophils graphic
    β-glucan causes CR3 to unfold into an intermediate state that may be ideal for safe and effective immune stimulation.

    Xian O’Brien, PhD and Kate Heflin, PhD, while earning their degrees in Reichner’s lab, found that β-glucan treatment causes the integrin to unfold into an intermediate state, and are testing the idea that this intermediate state represents an ideal therapeutic state in which the neutrophil may be able to migrate to a source of infection and destroy a pathogen without causing tissue damage.

    Courtni Newsome, PhD, who also performed her thesis work in Reichner’s lab, showed that a potential benefit of β-glucan may be in helping the immune system combat systemic infections. Mice treated with β-glucan survived whole body infections, known as sepsis, better than untreated animals. Systemic infections can occur following traumatic injury, and β-glucan may become a new type of infection fighting drug.

    Another reason to study β-glucan is demonstrated by Angel Byrd and Courtney Johnson, two students working toward their combined MD-PhD degrees in Reichner’s lab. Like bacteria, certain fungi can cause life-threatening infections. Because β-glucan is present in fungal pathogens, it serves as an ID card for neutrophils to identify the fungi as foreign. Once CR3 binds to the β-glucan within the fungi, the neutrophil becomes activated to kill the fungal invader.

    “There are few times in the life of a basic researcher when you even get in the game, when what you think and what you work on can be translated into understanding a disease or developing a new medicine that can actually improve people’s health. This is one of those times. β-glucan has the potential to become a new class of medicine, extracted from a naturally occurring source and able to improve immune health without serious side effects.”