Investigating the Role of PIKfyve in the Immune Function of Neutrophils
By Connie Jeske Crane
Anytime we get a small cut, a virus or a bacterial infection, a set of powerful and complex immune responses is unleashed within our bodies. While there’s much we do understand, scientists continue to make important discoveries about the human immune system.
At Ryerson for example, a team from the Department of Chemistry and Biology, supervised by Dr. Roberto Botelho, recently completed some notable research in this area. The team – which included Roya Monica Dayam, who recently earned a PhD in Molecular Science at Ryerson, and fellow researchers Chun X. Sun and Christopher Choy – wanted to get a better understanding of what drives neutrophils to seek and destroy infections.
So what are neutrophils? As Dayam explains, when humans get an infection, “neutrophils are immune cells that are usually first to arrive at a site of infection because of their unmatched ability to ‘chemotaxe,’ which means they can ‘smell’ and migrate towards the source of infection signals.” Once they arrive at the infection site, neutrophils unleash a variety of attacks on the microbes, says Dayam. This includes, “mounting a devastating chemical attack that uses bleach and free radicals and literally eating them, a process called phagocytosis.”
Specifically Dayam and her fellow researchers decided to focus on the importance of one specific lipid in neutrophils – lipid kinase PIKfyve – and investigate its role in the immune function of neutrophils. “PIKfyve is an enzyme that generates a signaling lipid called phosphatidylinositol-3,5-bisphosphate, which controls organelles called lysosomes that encase digestive enzymes,” says Dayam, adding that to the team’s knowledge, they are the first researchers to investigate this aspect of PIKfyve.
The Figure shows human neutrophils treated with PIKfyve inhibitors (Ap, YM) fail to make phagosomes degradative (A, B) and impairs their ability to move towards an infection signal (C, D).
Ultimately the team’s experimentation, which involved both human and mouse neutrophils, revealed fascinating processes at work. “It showed that PIKfyve inhibition curtails neutrophil function, including chemotaxis, phagocytosis and even mounting a chemical attack,” says Dayam. She says PIKfyve appears to play a role in stimulating another enzyme called Rac GTPase, a master switch for chemotaxis, phagocytosis and free radical production.
As is often the case, the work revealed further questions for Dayam and fellow researchers. “We now need to understand how PIKfyve and Rac talk to each other, which will require additional studies,” says Dayam. For the researchers, the end goal with investigations here, says Dayam, is to better understand what drives neutrophils to seek and destroy infections and why this can backfire during inflammatory diseases.
At Ryerson, Dayam was a passionate and involved student; among other involvements she served as the vice president of finance of Gradate Course Union (GCU) and organized the Toronto Organelle Function and Dynamics (TOOFAD) research conference. Looking back, she values the many opportunities for interaction and the Ryerson lab environment. “The unconditional help and support from our lab members made research more fun and enjoyable.”
With her grad studies complete, Dayam moved south of the border in May, and is currently a post-doctoral fellow at Harvard Medical School in Boston, Mass.
The Ryerson team’s research was funded through several of Dr. Botelho’s grants including NSERC, Canada Research Chair and Ontario government Early Researcher Award funds.