A tug-of-war in your immune system

GlycoNet Investigators are looking into using carbohydrate-binding proteins to help battle fungal pathogens

By Ali Chou

In a world where drug-resistant pathogens are more and more common, Aspergillus is having a field day. We breathe the spores of this airborne fungus every day. Most people won’t get sick from it. People with weakened immune systems, however, are at higher risks of developing health problems from breathing in these spores. As a result, they may experience symptoms including allergic reactions and pneumonia. To some, this may even be fatal.

If we breathe the same air, why is the risk of illnesses higher for those who are immunocompromised? It turns out there is a constant tug-of-war between pathogens and immune cells within our immune system. In healthy individuals, white blood cells called “neutrophils” patrol around looking for spores, swallow them and kill them. In immunocompromised patients—patients undergoing cancer therapies, transplant recipients or those with diabetes and HIV/AIDS—neutrophils become relatively inactive, giving way to pathogens to kill healthy cells. Every year, over 1.5 million people fall ill because invasive fungi win the battle against neutrophils.

GlycoNet Investigators Dr. Sachiko Sato from the Université Laval, Dr. James Rini from the University of Toronto, and Dr. Don Sheppard from McGill University are looking for ways to defeat these fungal pathogens. Instead of developing anti-fungal agents that may be quickly outrun by the pathogen’s evolving drug-resistance, they are using a natural agent present in human beings to boost the ability of neutrophils to do their job.

This natural agent is a carbohydrate-binding protein called galectin-3.

“When we breathe pathogens (into our lungs), our bodies sense foreign matters and release galectin-3; this protein is known to be involved in the signaling pathways to tell the body to prepare for a series of immune response,” says Sato.

One of these responses consists of the body sending a signal to prompt neutrophils to go to the infected site. After the signal is sent, galectin-3 facilitates the migration.

However, their preliminary results suggest that some immunocompromised patients may not have the capacity to produce enough galectin-3. Moreover, these patients’ bodies are under immunosuppressive conditions that reduce neutrophils to migrate to their lungs.

Sato and her team found that, from animal model studies, the lack of galectin-3 prevents neutrophils from being directed to the infection site. This finding may indicate the reason why immunocompromised patients are more susceptible to air-borne fungal infections. To improve this situation, Sato and her team proposed developing galectin-3 into an aerosol drug, and to deliver it to patients’ lungs to boost their immune system. “The increased concentration of galectin-3 in the lungs may be able to signal to the neutrophils to migrate over and destroy pathogens,” explains Sato.

Typically, the research process begins with in vitro experiments (experiments performed in a place outside a living organism) and later on moves to in vivo testing —Sato explains this project started directly at the in vivo stage with mouse models. The team was able to accelerate the normal process because of the breadth of the collaboration.

“Dr. Don Sheppard is playing a key role in the success of the project,” says Sato. “He is an expert when it comes to fungi infections in the lungs. His lab plays a critical part in all the in vivo experiments. Our lab, on the other hand, supports from the point of view of glycobiology, where we accumulated knowledge of galectin-3, neutrophils, as well as deep understanding of host-pathogen interactions. In addition, some detailed biochemical approaches are performed in collaboration with Dr. James Rini.”

Sato points out that the project is not only leading to the development of a natural boosting agent to enable the immune system to fight off fungal pathogens. It also inspired her to investigate other uses for galectin-3.

“We found that galectin-3 is also heavily involved in the generation of muscle fibres (myogenesis), and this gives us ideas of leveraging this protein to treat patients suffering from Duchenne muscular dystrophy,” says Sato.

Duchenne muscular dystrophy is a genetic disorder characterized by progressive muscle degeneration and weakness. Sato thinks that augmenting the signaling of galectin-3 in the body may be a possible way to treat these patients and make them generate muscles. 

“But I’m not talking about directly injecting galectin-3 into the patients,” says Sato. “Since 40% of our body mass is muscle, if we inject an equivalent amount of galectin-3 as the treatment, it would be very pricy.” She is working on an alternative solution.

“Similar to the idea of using a carbohydrate-binding protein (galectin-3) to boost the immune system, we decide to deliver a carbohydrate molecule that will trigger a series of signaling responses, and eventually incentivizes the body to make more galectin-3, thereby increasing the activity of galectin-3 in patients with muscular dystrophy.” she says.

From restoring immune balance to boosting the body’s power to fight off pathogens, Sato and her team are making significant headways to solve the issue of antimicrobial resistance. Their next step, says Sato, is to investigate the formulation of the aerosol so that it can efficiently be delivered to patients’ lungs. They hope that the completed, formulated aerosol drug will benefit hospitalized patients as their bodies fight invasive fungi.