Date Published: 8 August 2005

How fungal microbes alter the appearance of their cell surfaces to slip past the immune system's defences.

Researchers at the Massachusetts Institute of Technology (MIT) located in Boston, USA, explain how fungal microbes can quickly alter the appearance of their cell surfaces, their "skin," disguising themselves in order to slip past the immune system's vigilant defenses. This work was been published in the online journal "Nature Genetics" on 7th August 2005.

The authors of this study reported that chemotherapy and organ transplantation not only take a huge toll on patients, but they can compromise the immune system and leave patients vulnerable to infections from microbes such as pathogenic fungi - the fastest-growing cause of hospital-acquired infections.

Researchers from MIT and the Whitehead Institute for Biomedical Research explain one possible reason why these fungal microbes are such a scourge.

According to MIT biology Professor Gerald Fink: "It's all about skin." He compared the structure of the fungal microbe to that of one of those small circular brightly coloured surgary snacks called M&Ms because there is a sugar coating encasing the cell's DNA and explained:

" The skin of fungi microbes is what enables them to stick to your organs and thus become pathogenic. It also enables the fungi to stick together, which is desirable for fermentation in beer."

The genetic core to this study is a DNA phenomenon known as tandem repeats.

Small units of between three and 200 nucleotides form within a gene and repeat sometimes up to about 35 times. Nucleotides, the building blocks of our genome, are represented by the letters A, C, T, G. In humans, these tandem repeats received a lot of attention when the gene responsible for Huntington's disease was discovered; a repeat of the letters CAG in a gene called IT-15 causes the condition.

These tandem repeats also occur in fungal microbes. Kevin Verstrepen, a postdoctoral researcher in Fink's lab, decided to find out how often they occur, and what possible functions they might offer, by using baker's yeast as a model. Verstrepen scanned the entire yeast genome with a custom computer program developed by Whitehead's bioinformatics group. He discovered that the repeats are common throughout the yeast genome, and that more than 60% occur in genes that code for cell-surface, or skin, proteins.

In other words,

"Most of these repeats somehow affect how the yeast cell interacts with the environment surrounding it," said Verstrepen.

In addition, he found that the length of these repeats varied greatly between a mother and a daughter cell. While one yeast cell might have a 20-unit repeat on a particular gene, when it divides, the new cell might have only a five-unit repeat on that same gene. And, when that new cell later divides, its daughter cell might go back to 20 repeats.

"It's like an accordion," said Verstrepen.
"Our study really showed how quickly and easily these repeats can recombine, altering the properties of the cell surface almost immediately."

This provides a significant clue to why fungal infections can be so deadly. The immune system generally recognizes invaders by signatures on their outer coatings, such as protein conformations. Fungal microbes that can quickly change the shape of these proteins by changing the number of repeats in the corresponding gene can manage to stay one step ahead of our body's defenses.

"It's important to remember," said Fink, "that these microbes have been around for billions of years. They haven't come this far without learning how to fight off predators."

Fink believes that these findings show why traditional approaches to targeting drugs won't work on fungal microbes. The features that drugs target may be exactly the ones that change so readily.

"We need to target other aspects to the cell surface that don't change," he said, and suggested that certain sugar molecules residing on the inside of the cell coating may be interesting targets.

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