Recent case reports and epidemiological data suggest fungal infections represent an under-appreciated respiratory co-infection among people with severe COVID-19, however the frequency and clinical impact is currently unknown. We have previously generated a single-cell RNA-sequencing (scRNA-seq) dataset characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity with the local behavior of nasal epithelial and immune cells. In agreement with other human cohorts, this prior study suggested that a deficiency in host immunity, particularly in type I/ III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. Here, we have performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent nasal and/or endotracheal infection with Candida spp. We present the clinical characteristics of these individuals, including confirmatory testing demonstrating elevated serum (1,3)-β-D-glucan and/or a positive fungal culture. Finally, using the matched single-cell transcriptomic profiles of these individuals’ respiratory mucosa, in addition to blunted type I/III interferon signaling previously reported, we identified epithelial and mucosal immune signatures consistent with augmented IL-17 responses, suggestive of activated anti-fungal immunity. These results indicate that a subset of patients with severe COVID-19 exhibit increased frequency of concurrent fungal infections associated with augmented IL-17 responses and suggest that concurrent fungal infection may be contributing to SARS-C0V-2 mediated inflammatory pathology.

This project has been made possible in part by grant number 2020-216949 from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation to Alex K. Shalek and Jose Ordovas-Montanes.  Carly G. K. Ziegler was supported by T32GM007753 from the NIH. Jose Ordovas-Montanes is a New York Stem Cell Foundation – Robertson Investigator. Jose Ordovas-Montanes was supported by the Richard and Susan Smith Family Foundation, the AGA Research Foundation’s AGA-Takeda Pharmaceuticals Research Scholar Award in IBD – AGA2020-13-01, the Food Allergy Science Initiative, and The New York Stem Cell Foundation. Bruce H. Horwitz was supported by DK122532-01A1, NIH; 12019PG-CD002, The Leona M. and Harry B. Helmsley Charitable Trust; SRA #54518, and Crohn’s and Colitis Foundation. P.L. was supported by 5T32AG000222 from the NIH. Andrew W. Navia was supported by the Ludwig Center for Molecular Oncology at MIT. Alex K. Shalek was supported by the Bill and Melinda Gates Foundation, Sloan Fellowship in Chemistry, the NIH (5U24AI118672), and the Ragon Institute of MGH, MIT and Harvard.