Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Authors

Leila B. Giron, The Wistar Institute
Michael J. Peluso, University of California, San Francisco
Jianyi Ding, The Wistar Institute
Grace Kenny, University College Dublin
Netanel F. Zilberstein, Rush University
Jane Koshy, The Wistar Institute
Kai Ying Hong, The Wistar Institute
Heather Rasmussen, University of Nebraska–LincolnFollow
Gregory E. Miller, Northwestern University
Faraz Bishehsari, Rush University
Robert A. Balk, Rush University
James N. Moy, Rush University
Rebecca Hoh, University of California, San Francisco
Scott Lu, University of California, San Francisco
Aaron R. Goldman, The Wistar Institute
Hsin Yao Tang, The Wistar Institute
Brandon C. Yee, Monogram Biosciences
Ahmed Chenna, Monogram Biosciences
John W. Winslow, Monogram Biosciences
Christos J. Petropoulos, Monogram Biosciences
J. Daniel Kelly, University of California, San Francisco
Haimanot Wasse, Rush University
Jeffrey N. Martin, University of California, San Francisco
Qin Liu, The Wistar Institute
Ali Keshavarzian, Rush University
Alan Landay, Rush University
Steven G. Deeks, University of California, San Francisco
Timothy J. Henrich, University of California, San Francisco
Mohamed Abdel-Mohsen, The Wistar Institute

Document Type

Article

Date of this Version

8-8-2022

Citation

JCI Insight 2022;7(15):e160989

https://doi.org/10.1172/jci.insight.160989

Comments

Copyright: © 2022, Giron et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Abstract

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as β-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.