Research reveals how neutrophils orchestrate the mobilization of zinc to fight microbes

A research team from Umeå University, Sweden, in collaboration with Ghent University, Belgium, has made a groundbreaking discovery about how the body's first immune defense, neutrophils, orchestrate the mobilization of zinc to fight microbes.

We show that immune cells drain microbes of zinc, making them more vulnerable. At the same time, the ability of neutrophils to kill microbes is clearly affected by how much zinc is available. Our results reveal the delicate balance of trace metals in the immune system."

Constantin Urban, Professor, Department of Clinical Microbiology, Umeå University

Neutrophils are specialized immune cells that respond rapidly to infections by capturing and destroying microbes - a process called phagocytosis. During phagocytosis, the cell surrounds the microbe with its membrane and forms a fluid-filled vesicle, a phagosome, where the microbe is digested.

Trace metals such as zinc, copper, and manganese are vital for the survival of all living organisms, from animals to microbes. During an infection, an intense struggle for these metals occurs, with both disease-causing microbes and the body's immune system trying to gain access to them. This phenomenon is called "nutritional immunity."

Until now, it has been uncertain whether neutrophils can extract zinc ions from microbes inside the phagosome. The prevailing hypothetical model suggests that neutrophils intoxicate microbes by pumping excess zinc into the phagosome.

To answer this question, Constantin Urban and his colleagues used cutting-edge high-resolution chemical imaging techniques to monitor the redistribution of zinc in real-time in neutrophils during phagocytosis. The study used the common model organism Saccharomyces cerevisiae - yeast.

Surprisingly, their data showed that the prevailing theory is incorrect.

"We can show that the movement of zinc is tightly coordinated by the neutrophils, which dynamically regulate the availability of zinc in the phagosome," says Nadeem Ullah, postdoctoral fellow at the Department of Clinical Microbiology at Umeå University.

The study shows that zinc levels affect the efficiency of neutrophils. When zinc levels were low, yeast cells were killed more efficiently, while high zinc levels in the phagocytized yeast cell significantly impaired the neutrophil's ability to fight microbes. This highlights the importance of a carefully regulated balance of trace metals for a strong immune response.

"Our findings open up new ways to strengthen the immune system," says Nadeem Ullah. By adjusting zinc levels, we could help neutrophils fight infections more effectively. Understanding how metals, especially zinc, affect immune cells could lead to new treatments for infections and conditions where immune function is weakened.

The research group now plans to continue with studies that focus on the molecular mechanisms behind zinc mobilization.

"In upcoming projects, we want to identify the membrane transporters that control the flow of zinc ions between the phagosome and the microbe," says Constantin Urban.

The study is published in the Journal of Biological Chemistry.