By: Carolyn Morris
Unlike the environmental extremes found in nature, our bodies are fairly stable homes for the trillions of microorganisms we host. Thanks to homeostasis, we keep things like temperature and acidity at regular levels. But we can turn up the heat and run a fever, especially in reaction to an infection. As it turns out, certain opportunistic pathogens — microbes that are normally harmless but can become life-threatening when our bodies are compromised — can thrive in response to this heat shock. In a study published today in Nature Communication, molecular genetics professor Leah Cowen reveals the molecular culprits and the circuitry involved in helping the opportunistic fungus Candida albicans respond to heat. She spoke with Faculty of Medicine writer Carolyn Morris about her findings.
What did you find out about how this fungus responds to heat?
We discovered that simply exposing Candida cells to a 10-minute heat shock, with a sudden upwards shift in temperature, caused the cells to become more destructive in multiple infection models. In response to the heat, Candida activates a transcription factor called Hsf1 — which is a protein that binds to specific sequences in DNA. In this case, it binds to over 100 target genes, controlling their expression and enabling a cellular response to cope with the temperature stress.
What we found was happening is that another protein that normally represses Hsf1 — what we call a “chaperone protein,” because it helps other proteins fold into shape — became so busy refolding proteins that were unraveling due to the increased temperature, that it stopped keeping Hsf1 in check.
In addition, this same chaperone protein was also involved in determining which segments of the DNA would be accessible to the Hsf1 transcription factor. It did this by influencing which areas of DNA are kept folded up tightly in packaging units called nucleosomes, and which areas are left unpacked. This explained why Hsf1 wasn’t binding to all the regions it should recognize.
So not only does this chaperone protein release its hold on Hsf1, it also gives it access to specific sections of DNA, helping to induce the heat shock reaction that makes Candida stronger and more harmful to its host.
Could you liken this to a teenager left home alone without supervision? As if the Hsf1 transcription factor, no longer under the thumb of its chaperone, carried out the cellular equivalent of a raucous house party — a heat shock response?
I’m not sure if the house party analogy works well. To me a teenage house party implies chaos and destruction, when in fact what we found was the opposite. Far from chaotic, this was an extremely orchestrated program required for survival, so protective in nature. I see it more as a carefully crafted scheme or escape plan — one that gets triggered into action when faced with the threat of increased temperature. It’s a great defense mechanism for Candida — but possibly not so great for its host.
What could your findings mean for how we treat pathogens like Candida albicans?
The findings make us revisit longstanding debates about the benefits of fever. Our results suggest that a very short fever might actually help the pathogen turn on programs that make it more dangerous. It may all be a matter of timing, though, considering that other studies we’ve pursued have shown that prolonged elevated temperatures can actually cripple fungal pathogens and make them more sensitive to antifungal drugs. While our studies raise very intriguing ideas about the impact of elevated temperatures on human pathogens, it’s important to recognize that conditions are very different within the human host. We would need detailed clinical studies to gain an appreciation of the actual therapeutic implications.
Are the same players involved in Candida’s response to heat also involved in other infections?
The core cellular regulators that our work focused on are highly conserved in the eukaryotic tree of life, which means they can be found even in species that are distantly related. This suggests that our findings may have broad relevance to fungal pathogens, and perhaps also protozoan parasites, such as those that cause malaria. Notably, fever is a very common response to diverse infections, so there are likely to be complementary mechanisms to respond to temperature fluctuations in bacteria and other microbes.
What do you hope to research next, based on these findings?
Our new work in this area will further probe how cells respond to prolonged elevated temperature. We are taking functional genomic approaches to identify all the genes that are important for cellular responses to high temperature. We’re hoping this will help us identify new strategies to cripple fungal pathogens.