1. SARS-CoV-2 Spike protein triggers gut impairment since mucosal barrier to innermost layers: From basic science to clinical relevance.
- Author
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Nascimento RR, Aquino CC, Sousa JK, Gadelha KL, Cajado AG, Schiebel CS, Dooley SA, Sousa PA, Rocha JA, Medeiros JR, Magalhães PC, Maria-Ferreira D, Gois MB, C P Lima-Junior R, V T Wong D, Lima AM, Engevik AC, Nicolau LD, and Vale ML
- Subjects
- Animals, Humans, Mice, Jejunum immunology, Jejunum metabolism, Jejunum pathology, Jejunum virology, Molecular Docking Simulation, Enterocytes metabolism, Enterocytes virology, Immunity, Innate, Cytokines metabolism, Disease Models, Animal, Male, Clinical Relevance, Spike Glycoprotein, Coronavirus metabolism, Spike Glycoprotein, Coronavirus immunology, SARS-CoV-2 physiology, SARS-CoV-2 immunology, COVID-19 immunology, COVID-19 metabolism, Intestinal Mucosa metabolism, Intestinal Mucosa immunology
- Abstract
Studies have reported the occurrence of gastrointestinal (GI) symptoms, primarily diarrhea, in COVID-19. However, the pathobiology regarding COVID-19 in the GI tract remains limited. This work aimed to evaluate SARS-CoV-2 Spike protein interaction with gut lumen in different experimental approaches. Here, we present a novel experimental model with the inoculation of viral protein in the murine jejunal lumen, in vitro approach with human enterocytes, and molecular docking analysis. Spike protein led to increased intestinal fluid accompanied by Cl
- secretion, followed by intestinal edema, leukocyte infiltration, reduced glutathione levels, and increased cytokine levels [interleukin (IL)-6, tumor necrosis factor-α, IL-1β, IL-10], indicating inflammation. Additionally, the viral epitope caused disruption in the mucosal histoarchitecture with impairment in Paneth and goblet cells, including decreased lysozyme and mucin, respectively. Upregulation of toll-like receptor 2 and toll-like receptor 4 gene expression suggested potential activation of local innate immunity. Moreover, this experimental model exhibited reduced contractile responses in jejunal smooth muscle. In barrier function, there was a decrease in transepithelial electrical resistance and alterations in the expression of tight junction proteins in the murine jejunal epithelium. Additionally, paracellular intestinal permeability increased in human enterocytes. Finally, in silico data revealed that the Spike protein interacts with cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC), inferring its role in the secretory effect. Taken together, all the events observed point to gut impairment, affecting the mucosal barrier to the innermost layers, establishing a successful experimental model for studying COVID-19 in the GI context., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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