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

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-{kappa}B signaling. Using an in vitro Dectin-1/NF-{kappa}B reporter model, we found that plasma from individuals experiencing PASC induced higher NF-{kappa}B signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-{kappa}B signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Severe COVID-19 Is Fueled by Disrupted Gut Barrier Integrity

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.