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Coloured scanning electron micrograph of Candida albicans yeast cells.

The yeast Candida albicans can play a part in regulating the immune system.Credit: Eye Of Science/SPL

An imbalance of fungi in the gut could contribute to excessive inflammation in people with severe COVID-19 or long COVID. A study found that individuals with severe disease had elevated levels of a fungus that can activate the immune system and induce long-lasting changes.

The work, published on 23 October in Nature Immunology1, raises the possibility that antifungal treatment could provide some relief to people who are critically ill with COVID-19.

“We know inflammation is driving severe disease,” says Martin Hönigl, a clinical mycology researcher at the Medical University of Graz in Austria, who was not involved in the study. This work, he says, provides a potential mechanism of disease-causing inflammation that might have been overlooked.

Inflammation insights

Trillions of microorganisms live in and on our bodies, helping us to digest food, protecting us from harmful pathogens and more. Although much of the microbiome consists of bacteria, past research has shown that the fungal portion — the mycobiota — interacts with the immune system, too2.

Previous studies have shown that many people with COVID-19 have guts with altered microbial make-ups and disrupted protective barriers, which could allow pathogens to enter the blood3,4. And some individuals critically ill with COVID-19 have contracted dangerous fungal infections in their lungs5.

Immunologist Iliyan Iliev at Weill Cornell Medicine in New York City and his colleagues wanted to further investigate the link between the mycobiota and COVID-19. The researchers examined blood from 91 people hospitalized with the disease in 2020. Almost three-quarters of these people had severe COVID-19, who received more than six litres of supplementary oxygen a minute or invasive mechanical ventilation, whereas the rest had moderate or mild disease.

Compared with 36 individuals who had never tested positive for SARS-CoV-2, people with severe COVID-19 produced about four times as many antibodies against three fungal species commonly found in the gut, including the yeast Candida albicans. A high prevalence of antibodies suggests that these people had elevated amounts of those fungi. Faecal samples collected in early 2021 from 10 people with COVID-19 also showed that they had higher overall levels of gut fungi, especially of Candida species, relative to 10 healthy individuals. For these people, the abundance of Candida was positively correlated with disease severity. The presence of some fungal species, C. albicans in particular, has been shown to activate the immune system6.

In a subset of people with severe COVID-19, the number of antibodies against C. albicans in their blood was linked to the number of immune cells called neutrophils, which can trigger inflammation.

When the researchers infected mice with C. albicans extracted from people with severe COVID-19, and then infected them with SARS-CoV-2, they observed that more neutrophils invaded the animals’ lungs and activated an inflammatory response than in mice with SARS-CoV-2 alone. If they gave these mice an antifungal drug, it lowered the number and activity of neutrophils.

Long-COVID theories

The study also found that people with severe COVID-19 continued to have raised levels of antibodies against C. albicans and neutrophil precursors primed to counter fungi long after they had recovered from the disease — up to one year later in some people. These factors hint that mycobiota changes during a SARS-CoV-2 infection could contribute to inflammation associated with long COVID.

“There’s a number of theories of what might trigger persistent symptoms after COVID,” says Aran Singanayagam, a respiratory immunologist at Imperial College London. “Microbial dysbiosis, either of the gut or the lungs, is one major theory that people are proposing, so I think this adds weight to that theory.”

Researchers agree that more work is needed to probe the link between gut fungi and COVID-19. It remains unclear whether the observed changes to the mycobiota in people with COVID-19 resulted from the disease or preceded it and made people more susceptible, says Singanayagam.

If future studies reveal more about the mechanisms involved, existing antifungal treatments could be repurposed to help people with COVID-19. Iliev hopes that this work will “make people start thinking about those common types of biology that we see in very different diseases and how we can leverage that”.

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