Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19

Takato Kusakabe, Woan Yu Lin, Jin Gyu Cheong, Gagandeep Singh, Arjun Ravishankar, Stephen T. Yeung, Marissa Mesko, Meghan Bialt DeCelie, Guilhermina Carriche, Zhen Zhao, Sophie Rand, Itai Doron, Gregory G. Putzel, Stefan Worgall, Melissa Cushing, Lars Westblade, Giorgio Inghirami, Christopher N. Parkhurst, Chun Jun Guo, Michael SchotsaertAdolfo García-Sastre, Steven Z. Josefowicz, Mirella Salvatore, Iliyan D. Iliev

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Original languageEnglish
Pages (from-to)1879-1889
Number of pages11
JournalNature Immunology
Volume24
Issue number11
DOIs
StatePublished - Nov 2023

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