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 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 to 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 neuro-toxic 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 to 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.
Source: Giron LB, Peluso MJ, Ding J, Kenny G, Zilberstein NF, Koshy J, Hong KY, Rasmussen H, Miller GE, Bishehsari F, Balk RA, Moy JN, Hoh R, Lu S, Goldman AR, Tang HY, Yee BC, Chenna A, Winslow JW, Petropoulos CJ, Kelly JD, Wasse H, Martin JN, Liu Q, Keshavarzian A, Landay A, Deeks SG, Henrich TJ, Abdel-Mohsen M. Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling. JCI Insight. 2022 Jun 21:e160989. doi: 10.1172/jci.insight.160989. Epub ahead of print. PMID: 35727635. https://pubmed.ncbi.nlm.nih.gov/35727635/