Bacteria may regulate fungus’ shift from friend to foe in the gut
Our bodies are teeming with diverse species of fungi, from our guts to our mouths.
One type of fungus, Candida albicans, commonly inhabits the mucosal surfaces of roughly one third of the population. While C. albicans is usually harmless, it can cause mucosal infections, such as vaginal yeast infections and oral thrush (i.e, an accumulation of fungus in the mouth). It may also lead to disseminated infections, including bloodstream candidiasis, which is particularly deadly and occurs in roughly 25,000 people in the U.S. each year.
“There is a need to understand how this shift to pathogenesis occurs, especially considering a majority of invasive candidiasis arises from Candida already present within the gut,” says Faith Anderson, a graduate student in the O’Meara lab in the Department of Microbiology & Immunology. Such knowledge could lead to therapies that prevent or treat invasive C. albicans infections.
Investigating fungal-bacterial interactions
What regulates C. albicans’ shift from harmless gut resident to deadly pathogen? It’s complicated.
“There is not a one-to-one interaction between microbes and their host”, Anderson notes. Rather, “the other microbes present in the gut will have a significant impact on the outcomes of these interactions.”
Our intestines are home not just to fungi, but also hordes of bacteria. Interactions between intestinal microbes can change their behavior and, subsequently, their relationship to their host. As such, C. albicans’ relationship with bacteria could influence its shift from friend to foe.
Says Anderson, “Bacteria may change the tools employed by C. albicans [during colonization] to impact the host response to the fungal cells.”
C. albicans’ arsenal of tools includes changing shape to adapt to different environments and secreting enzymes that harm host cells. The surface of C. albicans is also decorated with long sugar molecules, called glycans, that serve as flags for immune cells to sense and respond to the fungi.
Interestingly, some gut bacteria eat glycans, including those found on the surface of microbes like C. albicans.
“It was previously demonstrated that Bacteroides thetaiotaomicron (B. theta)—a bacterium present in the guts of about 50% of Western populations—can degrade glycans made by Candida. However, these experiments were done using purified cell wall components,” says Anderson. Whether “B. theta can degrade glycans while they are still on the C. albicans cell wall,” has yet to be explored.
By pruning glycans on C. albicans’ surface, bacteria like B. theta may alter how immune cells see and engage with the fungi (i.e., do they tolerate its presence or sound the alarms?), and thus infection outcomes.
To explore this, Anderson grew C. albicans with B. theta in the lab and examined the effects on the fungal cell wall. Surprisingly, her findings suggest that B. theta promotes an increase in the number of glycans on C. albicans surface. One type of glycan, “mannan”, which forms the outermost layer of the cell, is particularly enriched. This is one of the first reports of an environmental pressure known to increase the mannan layer of C. albicans.
“Mannan is traditionally thought of as a ‘shield’ that limits the ability of host cell receptors to access underlying glycan layers of the fungal cell, which elicit an immune response,” she says. “We would think that more mannan results in a lower response” by restricting immune cell access to those particularly stimulating glycan varieties.
However, Anderson notes, “our preliminary results indicate that macrophages, a type of immune cell, are able to recognize and respond more rapidly to C. albicans following co-culture with B. theta.”
Notably, these results suggest that C. albicans’ ability to attract or evade an immune response may depend on its relationship with bacteria, like B. theta. Nevertheless, how bacteria influence the number and types of glycans on C. albicans’ surface, and what this means in terms of infection response and severity, warrants further investigation.
Next steps
Moving forward, Anderson hopes to determine how different host immune cells respond to C. albicans after co-culture with bacteria. These insights could inform methods to therapeutically exploit specific bacterial-C. albicans’ interactions that promote immune detection and clearance of the fungi. As such, she also aims to explore how broad C. albicans response to bacteria is, given the gut is home to thousands of different types.
With this in mind, Anderson believes her findings broadly highlight the mechanistic underpinnings, and significance, of studying microbe-microbe interactions in the gut.
“A lot has been done to characterize what the presence of certain microbes mean for human health,” she says. “We are building upon this work to begin to understand the mechanisms behind such interactions.”