Gut microbiota may contribute to the excessive inflammatory immune response of severe COVID, revealing implications regarding the potential therapeutic value of antifungal treatment in response to infection, new research has found.
The authors found increased levels of antibodies to gut fungi, but not lung or skin fungi, in individuals with severe COVID and even though this was not observed in those with a more moderate form of the disease, they suggested that a direct viral infection of the gastrointestinal tract could be driving fungal dysbiosis to promote both acute and chronic sequelae in COVID.
Fungal microbiota is known to activate immune responses and the study, published in Nature Immunology, built on past research demonstrating that individuals with COVID were more prone to altered gut microbial composition and gut barrier dysfunction.
Lead author, Associate Professor Iliyan Iliev from NY’s Weill Cornell Medicine, explained that fungal dysbiosis, particularly through the expansion of C. albicans, augmented inflammation during SARS-CoV-2 infection by increasing the movement of bacterial products and toxins into the blood, exacerbating the inflammatory response.
“The levels of antibodies to fungi correlated with an increase in the biomass of Candida albicans in the intestine and increased frequency of neutrophils in the blood of individuals with severe COVID,” he said.
“In addition, the stem cells that give rise to neutrophils, were primed to respond to fungi up to a year after disease recovery and in mice colonized with C. albicans strains isolated from individuals with severe COVID, neutrophil infiltration, and activation in the lungs after infection with SARS-CoV-2 was partially resolved by antifungal treatment or by the blockade of the inflammatory mediator IL-6.
“Individuals with COVID have increased risk of invasive candidiasis, pulmonary aspergillosis and mucormycosis, highlighting how commensals of the human mycobiome can cause fungal disease in those infected with SARS-CoV-2.”
Associate Professor Iliev and his team examined the gut microbiota of 91 individuals with COVID from three US cohorts recruited during the first wave of the pandemic. Of these, 66 were classified as having severe COVID, 25 had moderate COVID, and their data was compared to 36 individuals who had never been exposed to the virus.
“Individuals with COVID had a specific immune response to yeasts that correlated with disease outcomes,” Professor Iliyan said.
“We also found provocative evidence that fungal dysbiosis and antifungal antibody titres persist beyond acute illness in patients with severe COVID.”
Specifically, the team used single-nuclear RNA sequencing to evaluate transcription for several fungal-related genes in hematopoietic stem and progenitor cells (HSPCs) and found C-type lectin receptors and their related downstream signalling molecules were increased in convalescent patients with COVID at 4–12 months after severe illness compared to healthy controls.
An opinion piece on the study, also published in Nature Immunology, by Dr Katherine Lagree and Dr Peter Chen from LA’s Cedars-Sinai Medical Centre, noted that despite intense research efforts, the mechanisms that drive post-acute sequelae of COVID remained undefined, and the lack of a biomarker delayed diagnosis and treatment of the disease.
“Whether these fungal and inflammatory signatures are lingering changes from severe disease or can be used to predict those with post-acute COVID is uncertain but is a thought-provoking question worth investigating further,” they said.
“Because C. albicans is a commensal commonly found in the stool of healthy individuals, the factors that push the balance from healthy immune maintenance to proinflammatory conditions caused by fungi in the gastrointestinal tract remain unclear.”