Temperature Adaptation as a Virulence Determinant for Fungal Pathogens

Nov. 30, 2018

For a bat to avoid white nose syndrome, it must stay warm and keep moving; if it begins hibernation, it falls prey to the deadly disease. While this may sounds like some weird version of Nightmare on Elm Street, this actually describes the relationship between bats and Pseudogymnoascus destructans, the culprit behind white nose syndrome. Though this particular fungus has not adapted to its hosts’ sometimes warm temperatures, hundreds of other fungal species have, allowing them to become pathogens of mammals.

Of the estimated 2-5 million different fungal species, about 300 can grow at 37°C and cause disease in humans and other mammals. Since only this small percentage (about 0.015-0.006%) of fungi is pathogenic to humans, temperature tolerance and adaptation are primary fungal strategies used to infect mammals. However, the maximum temperature of P. destructans growth is 15°C—does this mean this fungus is an exception for temperature adaptation as a virulence determinant?

From Environmental Colonizers to Human Pathogens

Organisms that can’t regulate their body temperature experience more fungal infections than do mammals and birds. Fungal pathogens cause the largest number of plant infections, leading to loss of 20-70% of crops every year. Insects also suffer from deadly fungal infections, which afflict 20 of the 31 orders of the class Insecta. Among these fungal infections of insects, the infection caused by Ophiocordyceps stands out because of its “creepy” nature. This pathogenic fungus is also known as the “zombie ant fungus” due to its ability to “control” the brains of ants it infects.

Since warmer hosts restrict fungal growth more effectively, it is possible that one of the reasons warm-blooded animals evolved elevated internal temperatures was as a form of “antifungal immunity.” Interestingly, a “fungal filter” during the Cretaceous period has been proposed to have allowed mammals to become the dominant large animal type, thereby preventing a second reptilian age. However, the small number of fungi that can grow at mammalian temperatures cause serious disease, including in people.

Of the estimated 300 fungi that have adapted to the human host, several have a more complex and intricate relationship with temperature and are considered dimorphic fungi. Dimorphic fungi are usually found in the environment as moulds (growing as a mat of multicellular hyphae), but upon entering the mammalian host and encountering a higher temperature, they transition into a yeast form (single cell morphology), which evades the immune response, increases dissemination and increases overall fitness in the host. The 6 recognized true dimorphic fungi include Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii and Talaromyces marneffei (previously known as Penicillium marneffei). Temperature sensing and tolerance also modulate morphology and growth in other fungi, even those not considered true dimorphics, like the opportunistic pathogen Candida albicans.  

How do temperature-tolerant fungi survive inside the elevated temperatures of mammalian hosts? Fungi must first sense temperature and respond to the environment by monitoring membrane dynamics and structure. Many fungi use RNA-thermometers to activate the machinery required for thermal adaptation. Elevated temperatures mean proteins may become denatured; one of the most common protective mechanisms fungi use to manage higher temperatures are heat-shock proteins, which help prevent this denaturation. Recently, heat-shock proteins, specifically HSP90, have been implicated in modulating virulence and drug resistance in C. albicans. The thermotolerance of the mold Aspergillus fumigatus, which can grow at temps up to 55°C, depends on its nuclear protein CgrA and the role CgrA plays in thermotolerant ribosome biogenesis. In other words, growth at elevated temperatures is a multifaceted ability that requires orchestrated detection of external temperature and activation or protection of many cellular processes.
Aspergillus fumigatus CgrA is required for thermotolerance and virulence in an immune suppressed murine model.
Aspergillus fumigatus CgrA is required for thermotolerance and virulence in an immune suppressed murine model.

A Series of Unfortunate Temperature Regulation and Adaptation Events

Unlike the fungi mentioned, Pseudogymnoascus destructans, the causative agent of white nose syndrome in bats, can’t grow at elevated temperatures. This fungus has recently received worldwide attention due to its devastating effects on bat populations. White nose syndrome is a catastrophic infection that manifests in hibernating bats and has been ravaging populations in North America and some parts of Europe. The effects of P. destructans have been so severe, that the regional extinction of the little brown myotis bat (Myotis lucifugus) was recently predicted.
A bad suffering from white-nose syndrome caused by P. destructans.
A bad suffering from white-nose syndrome caused by P. destructans.

The story of P. destructans doesn’t involve fungal adaptation to elevated temperatures, but rather the fungus exploiting an animal behavior that lowers its internal temperature. P. destructans optimally grows at temperatures ranging from 1-15°C, but bats maintain a temperature of 37-41°C when active, warding off fungal infection. The situation changes when bats begin hibernating: during this time, their temperature drops to between 10-13°C. Now well within P. destructans’ optimal range, the fungus can infect its vulnerable host.

The fungus invades the skin of the ears, muzzles and wing membranes, causing irritation and damage. The infection causes the bats to become dehydrated and awaken from hibernation early; shortening hibernation leads to a depletion of fat storage in bats before insects, their primary food source, become readily available. Currently, the only management strategy available is to close hibernation caves to visitors in order to prevent spreading the fungus.
Pseudogymnoascus destructans.
Pseudogymnoascus destructans.
Source: Courtesy David Blehart, USGS National Wildlife Health Center

Adaptation to temperature has allowed fungi to thrive in almost any environment known. In the case of Chaetomium thermophilum, that environment often involves temperatures of 60°C, while Geomyces pannorum lives and grows at -2°C! This adaptation has permitted fungi to take crucial roles in the environment as decomposers and in some cases, as opportunistic pathogens. Although we are beginning to understand how these temperature-sensing mechanisms function, we are nowhere near the whole story.

Temperature Tolerance: Needed for Fungal Pathogenesis in Mammals

Most fungi that cause mammalian disease have clearly developed molecular mechanisms to detect and protect themselves at elevated mammalian body temperatures. It may seem that P. destructans is the exception to this rule, but its ability to cause disease in bats relies not on fungal adaptation, but fungal exploitation of lowered animal temperatures. To cause invasive disease in mammals, fungi must either develop strategies to tolerate elevated temperatures, or wait for a time when temperatures are no longer elevated—no exceptions (yet).

Further Reading

ASM Press: The Fungal Kingdom

mBio: Phylogenetics of Fungal Infection: Origins and Widespread Dispersal of White-Nose Syndrome

mBio Commentary: Breaching Pathogeographic Barriers by the Bat White-Nose Fungus


Author: Jesus Antonio Romo

Jesus Antonio Romo
Jesus Antonio Romo is a fourth-year doctoral candidate in the Cell and Molecular Biology (Microbiology and Immunology track) at The University of Texas at San Antonio (UTSA), where he is finishing his PhD (spring 2018) at UTSA working in a medical mycology laboratory with the fungus Candida albicans studying biofilm formation, drug discovery and development.