Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation

Abstract

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation - measured as beta-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 beta-glucan correlated with higher levels of markers of 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, beta-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-kB signaling. Using an in vitro Dectin-1/NF-kB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-kB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-kB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

“…The concept of microbial translocation as a key mechanism of chronic systemic immune activation, and disease was studied extensively in the HIV infection, a condition associated with chronic fatigue and increased prevalence of ME/CFS [294,295]. COVID-19, like HIV, causes intestinal barrier disruption, impaired efferocytosis, and accumulation of senescent, apoptotic, and necrotic cells that were previously associated with dysfunctional immune responses [296,297]. Indeed, the newly discovered innate lymphoid cells 3 (ILC3) that release interleukin 22 (IL22), a protector of intestinal barrier, have been implicated in both COVID-19 and HIV, linking dysfunctional mucosal immunity to these viral infections [298,299].…”