This article was written by student Hannah Wilson, the first place winner of the 2019 Annual Report Science Writing Contest, a competition held to highlight our best student writers. Wilson is affiliated with the Program in Microbiology and Infectious Diseases and her advisor is Michael C. Lorenz, PhD.
It’s 2019 and the buzzword “microbiome” has officially gone mainstream. As a microbiologist, I’m too familiar with the hype. Yet, most people don’t venture far past probiotics and kombucha when reflecting on their microbiome, and almost never do they acknowledge the fact that it’s composed of a domain of organisms other than prokaryotes. This invisible branch of your being is not only composed of bacteria, but microscopic fungi as well. These fungi make up a smaller subset of the microbiome, referred to as the human mycobiome, which receives considerably less media attention. The truth of the matter is that you (and your cellular constituents) are a dynamic ecosystem. What you consider to be “you” at the cellular level is only about 50% you, and the other 50% are microorganisms. Cell per cell, you and your microbiome exist in nearly equal numbers. Collectively, these human-dwelling bacteria and fungi can live as mutualists (both you and the microorganisms benefit from the relationship), or as commensals (they benefit from the relationship while you are neither helped nor harmed).
The fungus that I study in the lab of faculty member Michael C. Lorenz, PhD, Candida albicans or C. albicans, doesn’t maintain the status quo when it comes to being a standard commensal organism; it’s actually an opportunistic pathogen. I tend to think of Candida as a fair-weather friend. If you are a healthy, robust host with a functioning immune system, C. albicans poses little risk to your health as a prevalent member of the human microflora. About 60% of people are colonized with C. albicans at various body sites, including the oral cavity, gastrointestinal and urogenital tracts, skin, and vagina. Most healthy carriers of C. albicans do not exhibit disease, and those that do typically experience a treatable infection confined to one area of the body, (such as in oropharyngeal thrush or vulvovaginal candidiasis, also called a vaginal yeast infection). However, should the host’s immune system become suppressed by chemotherapy, radiation, implanted medical devices, or a menagerie of other modern medical interventions, invasive disease caused by C. albicans can become a frightening reality. The once harmless member of the microbiota can become a legitimate health concern with a mortality rate of roughly 40% for bloodstream infections.
Once the innate immune system (which serves as the body’s first line of defense) is compromised, this fungus can undergo a critical transition. It shifts from being a contained, benign constituent of the microbiome to an invasive pathogen that can disseminate into the bloodstream and tissues. In order to do this, it undergoes a change in morphology and engages a different gene expression program that promotes infection rather than commensalism. In simpler terms, C. albicans changes its shape and behavior based on whether the human host is vulnerable or not, and from an
evolutionary perspective, it seems to know exactly what it’s doing.
Though we know that this shift occurs, we as molecular biologists don’t fully understand the mechanisms that contribute to C. albicans’ ability to drastically change lifestyles and propagate in this manner. The interactions that C. albicans shares with immune cells are complex, dynamic, and two-sided. For example, in our lab we are interested in the C. albicans-macrophage interaction. Macrophages phagocytose C. albicans and create a hostile environment within the phagolysosome, which serves as a cellular stomach for the immune cell. The macrophage acidifies the phagolysosome, introduces an influx of reactive nitrogen and oxygen species, and releases antimicrobial peptides into this compartment to eliminate microbial threats. In addition to the hostile compounds that C. albicans is exposed to here, the environment itself is incredibly nutrient-poor. Sounds like a definite death sentence for a pathogen, right? This is where C. albicans rises to the occasion. Triggered by environmental cues, C. albicans responds to the cellular offenses by releasing proteases, superoxide dismutase, and catalase in addition to other beneficial mediators. It also alters its gene expression to engage metabolic processes that are specific to the limited carbon sources available within the macrophage. These alternative metabolic pathways are dual-purpose as they also enable C. albicans to counteract the acidification of this space, making it more conducive for the fungus to survive and escape. Lastly, C. albicans can induce the formation of hyphae, which are elongated filaments branching from the fungal cell wall. The hyphae can force a hole through the phagolysosome and ultimately facilitate C. albicans’ escape from the macrophage.
This dynamic interaction with the macrophage is hardly representative of C. albicans’ full disease- causing repertoire. We know that C. albicans is able to sense and respond to a variety of signals at the host- pathogen interface, but we are only just beginning to unravel the details governing these interactions. Comparative transcriptomic analysis has led us to a set of uncharacterized genes in C. albicans that are highly upregulated upon macrophage phagocytosis. We hypothesize that many of these open reading frames of DNA are crucial mediators of virulence and part of my dissertation work is to investigate them further. I am seeking to pinpoint and characterize the mechanisms by which C. albicans evades the immune system and causes invasive disease. My long-term goal is to identify cellular targets for the development of vaccines and therapeutics that will contribute to improving patient outcomes. The lack of antifungal drugs available in conjunction with the rising prevalence of drug resistance seen in C. albicans make this infection dangerous for a patient who is already critically ill.
So the next time you find yourself thinking about your microbiome, take a moment to acknowledge it for what it truly is: a jungle of complex biodiversity. Among the skin, hair, mucous membranes, and gut, C. albicans lurks, and thousands of other species compete to adapt and occupy a niche. The relationships we share with our microbes are dynamic and conditional, completely unique to each individual, and most notably, out of our control. We are all just petri dishes with shoes, surprisingly subject to the invisible organisms we host.