An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection

Computational Methods Computational Methods
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Andrew Navia Andrew Navia
Carly Ziegler Carly Ziegler
Josh Bromley Josh Bromley
José Ordovas-Montañes José Ordovas-Montañes
Micayla George Micayla George
Riley Drake Riley Drake
Sam Kazer Sam Kazer
Vincent Miao Vincent Miao

Ziegler et al.▾ Ziegler, C. G. K., Owings, A. H., Galeas-Pena, M., Kazer, S. W., Miao, V. M., Navia, A. W., Tang, T., Bromley, J. D., Lofty, P., Sloan, M., Laird, H., Williams, H. B., George, M., Drake, R. S., Pride, Y., Abraham III, G. E., Sentiko, M., Robinson, T. O., Diamond, G., Lionakis, M. S., Shalek. A. K., Ordoves-Montanes, J., Horwitz, B. H., Glover, S. C.

American Society for Microbiology

May, 2024


Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candidaspecies-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals’ respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation—in part driven by Candida colonization—and blunted interferon signaling represent a common feature of severe COVID-19 infection.