Fungi are an indispensable part of your microbiome, keeping the body’s host of microorganisms healthy as part of a system of checks and balances. But when you’re hit by an infection, fungi can be thrown out of equilibrium with other organisms inside you, leading to a more severe infection and other symptoms of illness.
For this reason, the pandemic immediately set off alarms for Iliyan Iliev, an immunologist at Weill Cornell Medical School. “We were thinking, the first thing that’s going to happen is people will start getting fungal co-infections,” he says. With the microbiome unbalanced, fungi might start running riot inside Covid patients, Iliev reasoned. His fears were soon realized.
In research published in Nature Immunology, he and his team discovered that in patients with severe Covid, certain strains of gut fungi—knocked off-kilter by the virus—set off a prolonged immune response that could last long after the initial infection. This response potentially led to some of the respiratory symptoms experienced by these patients. These results, Iliev says, point to the critical role of the gut microbiome in the human immune response and could lead to better disease treatments down the line.
Imbalance of the gut microbiome has long been linked to disease. Ken Cadwell, an immunologist at the Perelman School of Medicine at the University of Pennsylvania, thinks of the microbiome as a metaphorical rainforest. “It’s a nice ecosystem—but if you cut down too many trees or bring in invasive species, you could make things go out of whack,” he says.
To see how the body’s internal fungi were affected during Covid and how this triggered the immune system, Iliev and his team started by looking at patients’ blood. After collecting samples from 91 people with Covid, they measured levels of antibodies against several fungi, to figure out if the body’s immune system was reacting against these. Significantly more anti-fungal antibodies, for instance, would indicate fungal overgrowth or invasion.
Takato Kusakabe, a postdoctoral fellow in Iliev’s lab and study author, ran plate after plate of experiments—a painstaking process—to quantify these antibody levels. The team found in patients with severe Covid, several fungi commonly found in the gut had increased antibodies against them (in comparison to uninfected people). Notably, these included Candida albicans, which is a common culprit of yeast infections. When the team then ran tests on fecal samples from 10 of the hospitalized Covid patients, these confirmed that the fungi being targeted by the antibodies were present in the patients’ guts—and at seemingly at higher levels than in uninfected controls, suggesting an imbalance in their microbiome.
Iliev recalls excitedly peering into the laboratory incubator to see the first round of fungal isolations. “The plate was full, with a lawn full of fungal organisms,” he says.
Now that they knew severe Covid was associated with an increase in certain gut fungi, the team wanted to figure out exactly how this would influence the body’s immune cells. It wasn’t long before they found something out of the ordinary—certain neutrophils (a subtype of white blood cell that fights off infection) were present in greater quantities in severe Covid patients compared to those with mild or no disease.
When the team infected mice with Candida albicans strains taken from the severely affected Covid patients, they discovered that the mice generated increased fungal antibodies and neutrophils. And when they then treated these infected mice with the common antifungal drug fluconazole, numbers of these fungal-induced neutrophils decreased—as did the quantity of fungal antibodies. This indicated that overgrowth of those fungi helped cause the number of neutrophils to rise, with the coronavirus itself kickstarting the process.
Neutrophils are an important part of the immune system, says Iliev, but excessive activity can lead to prolonged inflammation that is characteristic of Covid. “Neutrophils will keep coming because they think there is inflammation and infection,” he adds. “They basically start exploding to make these structures called neutrophil extracellular traps—which, instead of helping you, actually makes the disease worse.”
And the impact of this fungal overgrowth didn’t end once the patients’ Covid had subsided. By looking again at blood samples from the severe Covid patients, and comparing these to samples from healthy controls, the scientists found that the stem cells that created these neutrophils had become specifically adapted to target fungi. These stem cells were active long after the initial infection, even after levels of fungal antibodies and neutrophils had died down—essentially priming the body to respond dramatically to a future fungal threat. At this stage, it’s not clear if this would be helpful or problematic for patients—it’s plausible that the patients’ bodies might be primed to overreact to other fungal infections in future.
There was one final question puzzling Iliev and his colleagues. How, then, did the fungi nestled in the gut cause such drastic changes in the immune system located elsewhere—all the way down to the stem cells? To answer that question, the scientists looked for signaling molecules, known as cytokines. One of these, called IL6, they noticed was elevated in the infected mice, alongside the elevated neutrophils and fungal antibodies. When the team blocked IL6, both the neutrophils and fungal antibodies decreased in quantity. “Maybe the mediator here is a cytokine that the fungi induce,” Iliev says, suggesting that these are potentially the sign of some communication across the body that sets all of these processes in motion.
This complex crosstalk between the gut microbiome and the immune system is an example of how most things in the body are intertwined, says Alessio Fasano, a gastroenterologist at Massachusetts General Hospital, who was unaffiliated with the study. “The gut is not like Las Vegas,” he says. “What happens in the gut does not stay in the gut.”
Fasano can envision this kind of work pointing to a future of more personalized medicine. Measuring for increased levels of fungal antibodies in Covid patients, he says, could potentially uncover a subset of people who might benefit from taking antifungal drugs like fluconazole.
All the scientists note, though, that it is unfair to assign the blame of upending the immune system to one single strain of fungi. Because the microbiome is always in flux, reestablishing balance after infection is key—throwing lots of antibiotics or antifungals at the problem can result in a never-ending game of biological whack-a-mole where one imbalance leads to another.
Now, Iliev and Kusakabe are interested in exploring how fungal overgrowth may appear in long Covid—and how immunity is affected. “What’s the impact of this reprogramming of the immune system by the fungus and the virus?” Iliev asks. “What happens long-term if you have suffered from that?”
