Fungi live around and inside us, but not every encounter leads to illness. Crick researchers are investigating how our immune system allows us to live alongside fungi through a delicate balance, recognising and clearing dead fungi without triggering damaging inflammation or allowing infection to take hold.
We are constantly exposed to hundreds of spores of fungi a day, mainly through the lungs, but we rarely develop fungal infections, despite this level of exposure. Our bodies have evolved to keep fungi in check without illness, but little is known about how the immune system deals with fungi without raising the alarm in ways that can cause harm.
Veni Papayannopoulos, who runs the Crick’s Antimicrobial Defence Laboratory, first became interested in how the body clears fungi after examining studies in mice. “After exposure, within a day the mice have huge amounts of fungi in the body,” he describes. “But after three days, it’s all been killed and removed, without causing the mouse to become unwell. I found this fascinating.”
Fungi are structurally much bigger than bacteria and viruses - they form large filaments called hyphae, which means they are too big to be taken in by the immune cells that kill them, like macrophages and neutrophils.
Veni has been awarded an Advanced Grant from the European Research Council.
In a new project funded through an Advanced Grant from the European Research Council, Veni is hoping to understand how our immune cells interact with and clear the debris of these large fungi, once immune cells have killed them.
“Immune cells need to detect, kill and clear fungal material in a specific part of the body without triggering a broader immune response that can drive damaging inflammation or allow infection to spread,” explains Veni.
“When this balance works, fungi are removed quietly. When it fails, infection and inflammation can take hold.”
In the new project, Veni’s team will use a combination of cell imaging techniques and immune profiling to understand which immune cells are involved in each part of the response to fungi, including how the dead hyphae are identified and cleared from the body quietly.
Veni also plans to interrogate how these systems are altered in people with recurring fungal infections, such as yeast infections or pulmonary aspergillosis, a group of lung conditions caused by inhaling spores of Aspergillus mould.
“Fungal infections are more likely to be harmful in people with chronic inflammatory conditions in the lungs, like COPD, asthma or cystic fibrosis,” says Veni. “We suspect a malfunction in the immune system causes a hypersensitivity to the fungi causing immune cells which normally dispose fungi to lose their tolerance and instead drive inflammation.”
mouse infection microscopy image showing hyphae (green) in the lungs (blue) with immune cells (neutrophils, magenta) attacking them.
WHO have declared fungal diseases to be an increasing public health concern, with common infections growing increasingly resistant to treatment and certain infections reaching very high mortality rates.
Veni’s team will work with both mouse models and human patient samples to look at how fungal disposal mechanisms protect healthy individuals from pathology and how defects in these pathways are implicated in persistent fungal infections.
“Understanding these protective mechanisms will not only give us insight into how the immune system deals with threats like fungi in healthy people,” concludes Veni. “It will also help us understand what’s different in persistent fungal infections and what we can do to improve the body’s response.”
