The Metamorphosis
A breath separates Blastomycetes dermatitdis from its ominous second nature: an inconspicuous mold in the soil, it develops in the lungs of mammals and humans into a pathological strain that can cause serious illnesses. The reason for the metamorphosis, however, lies in the dark. For most living beings, temperature fluctuations are certain death. Neither prolonged cold nor unduly warm ambient temperatures enjoy widespread enthusiasm in our earth kingdom, numerous organisms have become extinct because they could not adapt to the changes in their environment.
A small group of soil dwellers - they belong to the sac fungi - have developed a very special mechanism to protect themselves against such a fate: temperature-dependent dimorphism.
In their normal environment, the soil, the sac fungi behave like moulds. They form aerial mycelia and conidia and reproduce by sporulation. However, if such a spore ends up in a warmer environment, for example because it has been inhaled, the microorganism suddenly turns into a yeast-like fungus, which lodges in the lungs with sprout cells and can thus trigger dangerous diseases.
In the US alone, the dimorphic fungi cause more than a million infections a year. They often remain in the body in a latent form long after a disease has broken out and, at the next opportunity, exploit a weakness in the immune system again to spread at the expense of the host. The mushrooms are therefore extremely dangerous, especially for people with a weakened immune system - the peaceful Dr. Jekyll evolves into the infectious Mr. Hyde at body temperature.
People have been puzzled for a long time as to what exactly causes this transformation. Now a research group led by physician and microbiologist Bruce Klein from the University of Wisconsin has taken a closer look at one of the shape-shifters: Blastomyces dermatitidis, the cause of blastomycosis affecting the lungs and skin.
Among the six known dimorphs, B. dermatitides was particularly suitable for this study. Because earlier experiments had already identified a suspicious gene: BAD1, which is activated during the conversion to the disease-causing fungal variant and therefore seems to be at least partly responsible for the pathogenicity.
The team therefore created 15,000 different mutants of the ascomycete, each with a different gene defect, with the help of an agrobacterium that can insert its own genes into the DNA of host plants, but also of other microorganisms. They hoped that the imported foreign genetic material would result in some fungal variants that showed no tendency to develop into a yeast fungus at body temperature.
And indeed: One of the mutants, whose BAD1 gene activity was reduced by the manipulation, did not transform into the typical pathogenic Piz variant when the ambient temperature increased, but instead developed pseudofungi: the transformation was blocked. In addition, the mutant suffered from several changes that negatively affected its survival - the conidospores of the fruiting body, for example, were not as infectious as those of the original strain of the fungus.
Klein and his team now examined the exact point at which the inserted sequence of the agrobacterium had changed the mutant DNA: The affected sequence encodes the protein histidine kinase. This very old enzyme reacts to environmental changes such as temperature fluctuations and exists in a wide variety of life forms. When activated, Klein and his colleagues conclude that the shape-shifters use it as a sensor that indicates the right time for the respective lifestyle change.
To confirm their hypothesis, the scientists created a variant of B. dermatitides that cannot produce histidine kinase because the associated DRK1 gene is switched off. Exposed to a temperature of 37 degrees Celsius, this mutant remained trapped in its typical soil-dwelling form and also showed all the changes of reduced BAD1 activity.
Deprived of its ability to change, B. dermatitides is a much friendlier fellow: infections of the lungs, tested on mouse models, were much more harmless than with wild strains of the fungus. Thanks to the discovery of the sensor function of the histidine kinase, the researchers now hope to be able to develop drugs that can reduce or prevent infections with the dangerous form of yeast. So that those infected are spared the permanent company of Mr. Hyde in the future.
