How do deadly molds attack the immune system of humans?

Aspergillus fumigatus is a not-so-friendly mold that has secured a spot in every nook and corner of our world. While it may be just another mold species to some, it holds a rather notorious distinction for us humans – Aspergillus fumigatus is capable of causing grave and often fatal infections.

The culprit behind the lethal prowess of this particular mold? A unique enzyme on the surface of its spores known as glycosylasparaginase.

Dangers of the Aspergillus fumigatus mold

The risky business of dealing with A. fumigatus is part of daily life for an international research team headed by Gustavo Goldman from the University of São Paulo in Brazil.

Their mission? Uncovering the secrets that make this mold species deadly. Goldman’s research primarily revolves around the surface proteins of these spores – the defense front that first encounters our immune system, usually through inhalation.

Spore secrets of the deadly mold

What do these surface proteins reveal? Olaf Kniemeyer, a proteomics expert from the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), shed some light on this question.

Kniemeyer’s proficiency in mapping and assigning functions to all proteins in a cell have led to the identification of potential targets for new therapeutic substances.

With Kniemeyer and his team’s expertise in phagocytosis – the process by which our immune cells engulf foreign invaders – the research team was able to closely observe the mold.

“Gustavo Goldman’s group was particularly interested in the surface proteins on the spores, as these are the first to come into contact with the immune system – usually through inhalation,” noted Kniemeyer.

Focus of the research

To crack open the spore mysteries, the team employed a rather innovative approach known as trypsin shaving.

This involved using trypsin, a protein-cleaving enzyme, to purge all proteins from the spore surface – think of it as exfoliating the surface of the spores. After this rigorous “cleanup,” the team analyzed the protein fragments left behind using a mass spectrometer.

Mold and the immune system

Upon comparing their findings to existing databases, the researchers discovered 62 proteins that were exclusively present on A. fumigatus spores and absent in closely related species. This hinted at some of these proteins’ potential involvement in the infection process.

The experts then created a library of 42 fungus mutants, with each mutant lacking a gene responsible for one of these proteins.

It was found that the mutant lacking glycosylasparaginase triggered an increased release of interleukin-1β – an ultra-potent protein that incites fever, inflammation, and an assortment of other immune responses – in immune cells.

Taming the body’s immune response

The absence of glycosylasparaginase on the fungal spores allows the immune system to release more of this pro-inflammatory substance, thereby ramping up the body’s defense against the pathogen.

This suggests that the fungus normally produces glycosylasparaginase to tame the immune response, enabling it to infiltrate the body nearly unchecked.

A study in mice supports this theory, showing that mice with an intact immune system launched a more vigorous attack against the fungus when the gene for glycosylasparaginase was switched off.

Implications for future research

The insights gained from the study of glycosylasparaginase and its role in mediating immune responses opens a plethora of avenues for future exploration.

Understanding how A. fumigatus manipulates host defenses equips researchers with the foundational knowledge needed to design effective therapeutic interventions.

By identifying the specific interactions between this mold and the immune system, scientists can develop targeted drugs or vaccines that enhance immune recognition and response, potentially leading to breakthroughs in treating or preventing infections caused by this mold.

Indeed, the elusive glycosylasparaginase on A. fumigatus spores seems to play a key part in the fungus’s standoff with our immune system.

However, the exact workings of this mechanism remain wrapped in mystery. Still, these findings open up avenues for developing new treatments for infections caused by A. fumigatus – an urgent need given the limited number of effective drugs currently available and the steadily spreading resistance to them.

The study is published in the journal Nature Microbiology. 

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