Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation
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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 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 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, β-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-κB signaling. Using an in vitro Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-κB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.
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SciScore for 10.1101/2022.04.12.488051: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Ethics: All research protocols were approved by the institutional review board (IRB) at University of California San Francisco (UCSF), Rush University, and The Wistar Institute. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Metabolites were identified either by accurate mass and retention time using an in-house database generated from pure standards or by querying the mzCloud database (www.mzCloud.org) with MS/MS spectral data and selecting matches with 50 or greater scores. mzCloudsuggested: (mzCloud, RRID:SCR_014669)All statistical analyses were performed in R … SciScore for 10.1101/2022.04.12.488051: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Ethics: All research protocols were approved by the institutional review board (IRB) at University of California San Francisco (UCSF), Rush University, and The Wistar Institute. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Metabolites were identified either by accurate mass and retention time using an in-house database generated from pure standards or by querying the mzCloud database (www.mzCloud.org) with MS/MS spectral data and selecting matches with 50 or greater scores. mzCloudsuggested: (mzCloud, RRID:SCR_014669)All statistical analyses were performed in R and Prism 9.0 (GraphPad). Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study has several limitations. The source of β-glucan in the plasma is not clear. Fungal translocation during illness can occur from both the gut and the lung (57). Examining the contribution of the gut microbiome (using stool samples and intestinal biopsies) and lung microbiome (using sputum and/or bronchoalveolar lavage) will be needed to determine the source of the fungal translocation during PASC and the fungal species contributing to it. It will also be important to examine fungal translocation and host metabolites in longitudinal samples (from different body fluids including cerebrospinal fluid) to determine whether, and for how long, elevated levels of microbial translocation persist after acute COVID-19. Another possibility to the persistent dysregulation is that the intestinal barrier’s resilience to common intestinal disruptors (such as excessive alcohol or oxidative stress) is lower during PASC, making these individuals more vulnerable to frequent common disruptors, which then can lead to the translocation of microbes that cause systemic inflammation. Finally, correcting for additional potential confounders will require validating our results in larger independent cohorts from varying geographic and demographic settings. Despite these caveats, this study, which is exploratory in nature, sheds light on the potential role of microbial translocation and dysregulation of host metabolic pathways related to NMDA receptor activation in the pathophysiology of PASC. By...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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