Researchers have identified a critical protein "switch" that enables immune cells to destroy a dangerous fungus, a discovery that could lead to new therapies for hard-to-treat fungal infections.
Norwich, UK – Scientists at the University of East Anglia, in collaboration with the Babraham Institute and the Universidade de São Paulo, have discovered how a specific protein, RAB5c, acts as a master control switch in immune cells called macrophages. This switch is essential for the cells to effectively neutralize the fungus Aspergillus fumigatus.
The Mechanism of Fungal Killing
- When a macrophage engulfs an Aspergillus spore, it forms a compartment called a phagosome.
- In a healthy immune response, this phagosome undergoes a series of steps: it becomes acidic, toxic, and triggers a process known as LC3-associated phagocytosis (LAP).
- The protein RAB5c was found to be crucial for assembling the V-ATPase acid pump, a molecular machine that harnesses oxygen radicals to kill the trapped fungus.
Surprising Findings
Without RAB5c, the immune cells actually produced more toxic oxygen molecules—but failed to direct them effectively. Despite this increased production, the fungus survived.
"The cells actually produce more toxic molecules, but they don't kill the fungus. It's like the immune system's weapons are firing, but they're not aimed at the target." – Lead Researcher
Experimental Evidence
- In mice with a disabled LAP-RAB5c pathway, the results were stark:
- Higher fungal loads accumulated in the lungs.
- More extensive lung damage was observed.
- Stronger inflammatory responses were triggered compared to normal mice.
Broader Implications
This discovery could lead to new therapies that enhance the body's ability to fight fungal infections, which are notoriously difficult to diagnose and often resistant to current drugs. The LAP-RAB5c pathway is also involved in killing viruses and bacteria, and plays a role in inflammation, cancer immunity, and autoimmune disorders.
Funding: This research was supported by the Biotechnology and Biological Sciences Research Council (BBSRC).