Where Did That Come From? Solving A Pandemic Mystery
In 2009, physicians in Tokyo identified a novel organism in the ear discharge of a 70-year-old patient. Genetic analysis revealed that the organism was a fungus of the genus Candida. In most healthy adults, Candida albicans exists within the microbiome that calls our mouth and gastrointestinal tract home. So long as this home remains undisrupted, C. albicans does little to disrupt us. This yeast, however, was not C. albicans. In fact, this yeast had never been identified before. The yeast was eventually named Candida auris, from the Latin word for ear.
In the next decade, C. auris would be found in more than people’s ears as it made a somewhat silent spread across the world. Well, maybe spread is not the right word. Spread implies that from the Japanese patient in 2009, C. auris hitched a ride on coattails and cargo ships, infecting any stops it found along the way. However, genetic data indicate that this is not the case. Instead, three separate clades of the fungus arose at almost the same time in East Asia, South Asia, South America, and South Africa (an additional clade has possibly been identified in Iran). Instead of spreading to these locales, it was almost like C. auris had always been there.
From its rise, C. auris gained a sour reputation for its drug-resistant tenacity in healthcare facilities. While the fungus typically only affects the immunosuppressed, in cases where it reaches the bloodstream it has a crude mortality rate of 45%. The New York Times described a case of C. auris in Manhattan in 2018; after the patient died, the hospital had to rip out ceiling and floor tiles to completely sterilize the room. Unlike viruses, which cannot reside outside of a host for long, C. auris can linger on surfaces for weeks. It makes little difference for most fungal pathogens if their home is inside or outside of our bodies, even if that makes us dispensable.
Today, C. auris has its own page on the CDC website and the media moniker of “superbug.” 718 cases were reported in the United States in 2020, clustering in New York, California, and the Midwest. The COVID-19 pandemic likely led to an increased incidence of C. auris infection thanks to crowded hospitals, reused PPE, and an excess of immunocompromised patients. Public health officials advise that containing Candida auris comes down to the judicious prescription of antifungal medications, early diagnosis, and efficient sterilization measures. However, a glaring question remains unresolved dating all the way back to the first case report in 2009. How did the Japanese patient get sick in the first place?
We’ve seen it in the news headlines all of last year. A family infection is traced back to a March wedding. A spike in COVID-19 cases is explained by a major holiday. Maybe we’ve done the math ourselves for other diseases, figuring that a case of food poisoning must have come from the hamburger and not the fries. When looking at infectious diseases, these chains of transmission are common and somewhat easy for public health officials or the everyman to sort out. However, once this chain of transmission becomes a global web of crisscrossing links, any hope of finding a “patient zero” is thrown out the window. However, that doesn’t stop us from being enthralled by the question of what started it all.
This curiosity explains why public interest is currently dominated by investigations of the “lab leak” hypothesis, which postulates that the COVID-19 pandemic originated from a laboratory accident in Wuhan. It also explains the obsessions of past disease investigations. In the 1980s, the media scapegoated Canadian flight attendant Gaëtan Dugas as the patient zero of HIV/AIDS in America (Dugas was exonerated by genomic data after his death). It’s easy to understand why these investigations enthrall us. For one, it’s always easier to find someone else to blame. Perhaps more importantly, it feels like these investigations belong inside the pages of a Nancy Drew novel. Indeed, the search for the origins of C. auris follows a similar winding road.
There are multiple scientific hypotheses that attempt to decipher where this fungus came from and why it only emerged as a pathogen so recently in human history. One hypothesis states that C. auris diverged into its separate geographic families due to continental drift several million years ago. Environmental disruptions such as famines, tsunamis, and human migration allowed C. auris to colonize human skin, even as it only became pathogenic in recent years due to the rising use of antiseptics. Another hypothesis states that C. auris may have emerged as a pathogen due to the introduction of the antifungal fluconazole in the 1980s. However, one hypothesis focuses on one of the principal environmental stresses of the past century: climate change.
Candida auris’ ability to live outside of our bodies for long periods of time points back to a commonality for many fungal pathogens: most of them have roles in the environment which allow them to reside outside of a host. While a few fungi such as C. albicans happen to have niches as commensals on the human body, most fungi evolved their most distinctive characteristics without giving human infection a second thought. In the laboratory, C. auris has been shown to survive predation by amoebas, which use a similar engulfing mechanism that immune cells known as macrophages employ to trap intruders. Along with other fungal diseases, C. auris’ ability to infect humans could be serendipitous, a reflection of our body’s however distant relationship to the ecosystem fungi evolved to survive in. However, if this is indeed the case, the question persists of why C. auris decided to emerge as a pathogen now, of all times. If previous analyses are correct in noting that C. auris is likely many million years old, what prevented us from noticing it sooner?
In 2005, before C. auris was first isolated, physician-scientist Arturo Casadevall published a paper on vertebrate endothermy, or the ability of mammals to maintain a set internal body temperature of 98.7°F (or 37°C in scientific communities). This is part of the reason why humans have to eat many more calories than their reptilian counterparts, a tradeoff that leads many scientists to wonder what benefit justifies such a steep energetic cost. Casadevall posited that the mass extinction event that wiped out the dinosaurs created a paradise for decomposing fungi, leading to an overabundance of fungal spores. Mammals could survive potential infection from the new kids on the block with high internal temperatures that scorched any cold-loving fungi attempting to invade. For any fungus or pathogen that could manage to survive at 37°C, mammals could employ a fever to raise body temperatures over 40°C (or over 100°F).
In the present day, the fungi that do manage to infect humans must then no longer be deterred by our hellish internal booby trap. These fungi are deemed thermotolerant fungi, either because they always have been resistant to high temperatures or recently acquired the trait in response to environmental pressures. A changing global climate is as good an environmental pressure as any.
In brief, the thermal mismatch hypothesis states that C. auris was likely originally a plant saprophyte that was distributed in areas around the world. Climate pressures caused populations to become tolerant to excess heat. These yeasts, now thermotolerant enough to survive on animals, hitched rides on avian hosts to humans in rural areas, which eventually brought the stowaways to major metropolitan hospitals. However, the theorists also acknowledge that other factors may be at play beyond just warming temperatures. Increased UV radiation as a result of climate change may have mutated the DNA of yeast populations, hastening the evolutionary process. Agricultural pesticide or fungicide runoff may have seeped into waterways, triggering C. auris’ hallmark antifungal resistance. The temperature would be just one factor that played into a panoply of pathogenesis.
This thermal mismatch hypothesis has been presented in several papers in the past decade, but by nature it is quite difficult to prove. Although some challenges have come from the fact that C, auris is not yet known to infect avian hosts, most scientists can agree that the changing global climate likely exacerbating C. auris, along with other infectious diseases. Newer evidence that could support thermal mismatch comes from the isolation of C. auris from the Andaman Islands in the Indian Ocean. This is the first instance in which the fungus has been found in an environmental sample, unconnected to a host. Interestingly, one of the isolates was susceptible to high mammalian temperatures, making it markedly different from most of its superbug brethren. This strain may be a key piece of support for thermal mismatch, as its existence suggests that thermotolerance was a recent development in the life of the species.
While an engaging logical exercise among experts, it can be difficult to see what application solving some pandemic mysteries holds for human benefit. “Lab-leak” hypotheses about the origins of COVID-19, while they cannot yet be ruled out entirely, can ring off as geopolitical fanfare and distractions to the global vaccination effort. Similarly, the villainization of Gaëtan Dugas as an HIV/AIDS carrier, in retrospect, seemed to be one step towards the moralization and stigmatization of HIV/AIDS status in the United States. These two examples do not seem to offer the most altruistic motivations for investigating a pandemic. Ideally, any disease mystery should be solved with the objective of preventing or preparing for future outbreaks. In the case of C. auris’ origins, blame hasn’t fallen on a single human or group of humans but rather the changing climate that the human race has initiated. The climate will likely continue to change in the next century; are there other environmental microbes simply waiting to adapt to the temperatures that suit our body best?
In another publication, Dr. David Engelthaler and Dr. Arturo Casadevall use the phrase “black swan event” to describe the emergence of most diseases. Said simply, the phrase is used to describe unexpected events with major consequences. COVID-19 was a black swan event hardly anyone in the United States could have predicted eighteen months ago. As Japanese doctors struggled to identify the yeast inside their patient’s ear twelve years ago, it was unlikely that they imagined the destructive impact it would have on ICUs worldwide. However, with enough hindsight, theorists can make black swan events like the rise of C. auris more predictable and preventable.
Note: The writer of this piece currently conducts research in the Casadevall Laboratory
