A group led by Professor Oliver Werz at the Friedrich Schiller University, Jena have identified the pathway responsible for the incredible pathogenicity of the Aspergillus fumigatus fungus. By blocking the production of chemical messengers, the fungus prevents the immune response of the mould.
The NHS characterises aspergillosis as a lung condition caused by the inhalation of mould spores commonly found in soil, compost, rotting leaves, dust, and damp buildings among other sources.
The prevalence of this mould means that it is inhaled by many, but tends to affect specific at risk groups, such as people with lung conditions like asthma and cystic fibrosis, those with weakened immune systems caused by immunosuppressant drugs after organ transplant or during chemotherapy, sufferers or prior-sufferers of tuberculosis, and people with HIV/AIDs. The symptoms of aspergillosis include shortness of breath, cough, wheezing, fever and weight loss.
The paper published in Cell Chemical Biology outlines the discovery, made by exposing immune cells from the innate immune system to synthetic gliotoxin.
Among the at risk groups, the condition carries a mortality rate of 30-95 per cent and can be a devastating diagnosis.
It was previously known that A. fumigatus owes its pathogenicity to gliotoxin, a mycotoxin, which has immunosuppressive properties, but the mechanism had not been solved until now. The paper published in Cell Chemical Biology outlines the discovery, made by exposing immune cells from the innate immune system to synthetic gliotoxin.
Neutrophilic granulocytes (neutrophils) are the most numerous white blood cells in the body and comprise the first line of defence against invading pathogens. When an infection is detected, they migrate to the infection site and phagocytose (ingest and destroy) the pathogen.
One of the most crucial aspects of this immune response is the migration of the neutrophils to the infection. Chemoattractants are the chemical messengers that guide the neutrophils, and they are produced by other immune cells at the infection site. This is where gliotoxin interferes with the immune response.
When an infection is detected, they [neutrophils] migrate to the infection site and phagocytose (ingest and destroy) the pathogen.
Neutrophils produce the chemoattractant leukotriene using two enzymes: 5-lipoxygenase and LTA4 hydrolase. Once made, leukotriene is secreted into the bloodstream to attract other neutrophils in a cascade that results in neutralisation of the pathogen. What Oliver Werz’s team discovered, was that gliotoxin inhibits the synthesis of leukotriene by inhibiting the LTA4 hydrolase, thus preventing the recruitment of other neutrophils.
The team from Friedrich Schiller University created a gliotoxin knock out strain of A. fumigatus, and showed that this mutant strain did not suppress leukotriene synthesis where the wild type (does express gliotoxin) strain did. The mutant strain was also compared to the wild type in lung tissue samples, where the wild type samples showed nuclear fragmentation correlating with apoptosis/necrosis of neutrophils on the sample site. The mutant gliotoxin negative strain did not cause damage to the neutrophils.
Gliotoxin has been hailed the most important airborne fungal pathogen of humans by the König et al. (2019) paper, which makes aspergillosis incredibly dangerous to members of the population with decreased immune function. The biochemistry of this molecule was previously unsolved, thus there has been no development of any therapy to intervene with this aspect of the immunopathology of A. fumigatus infection.
The new understanding of this mechanism of immunosuppression is extremely important in the context of anti-fungal research.
This post was written by Molly Eastol and edited by Karolina Zieba.
