When the team infected mice with Candida albicans Using strains taken from severely affected Covid patients, they found that the mice generated an increase in fungal antibodies and neutrophils. And when they then treated these infected mice with the common antifungal drug fluconazole, the number of these fungal-induced neutrophils decreased, as did the number of fungal antibodies. This indicated that the overgrowth of these fungi helped the number of neutrophils increase, and the coronavirus itself started the process.
Neutrophils are an important part of the immune system, says Iliev, but excessive activity can lead to prolonged inflammation, characteristic of Covid. “The neutrophils will continue to come because they believe there is inflammation and infection,” he adds. “They basically start exploding to create these structures called neutrophil extracellular traps, which, instead of helping, actually make the disease worse.”
And the impact of this fungal overgrowth didn’t end once patients’ Covid subsided. By again looking at blood samples from severe Covid patients and comparing them with samples from healthy controls, the scientists discovered that the stem cells that created these neutrophils had specifically adapted to attack fungi. These stem cells remained active long after the initial infection, even after levels of fungal antibodies and neutrophils had decreased, essentially priming the body to respond dramatically to a future fungal threat. At this stage, it is unclear whether this would be helpful or problematic for patients; Patients’ bodies may be primed to overreact to other fungal infections in the future.
There was one last question that puzzled Iliev and his colleagues. So how is it possible that fungi lodged in the intestine caused such drastic changes in the immune system located elsewhere, all the way down to stem cells? To answer that question, scientists looked for signaling molecules, known as cytokines. One of them, called IL6, they noticed was elevated in the infected mice, along with elevated levels of neutrophils and fungal antibodies. When the team blocked IL6, both neutrophils and fungal antibodies decreased in quantity. “Maybe the mediator here is a fungal-induced cytokine,” Iliev says, suggesting that these are potentially a signal of some communication throughout the body that sets all these processes in motion.
This complex interaction 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 not involved in the study. “The gut is not like Las Vegas,” he says. “What happens in the intestine does not stay in the intestine.”
Fasano can imagine this type of work pointing to a future of more personalized medicine. According to him, measuring elevated levels of fungal antibodies in Covid patients could uncover a subset of people who could benefit from taking antifungal drugs such as fluconazole.
All scientists point out, however, that it is unfair to attribute the blame for altering the immune system to a single strain of fungi. Because the microbiome is always in flux, restoring balance after infection is key: Throwing too many antibiotics or antifungals at the problem can result in an endless 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 is the impact of this reprogramming of the immune system by the fungus and the virus?” Iliev asks. “What happens in the long term if you have suffered that?”
