ABSTRACT
Monitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. Here, we sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia from March to August 2020. We show that two consecutive mutations (R203K/G204R) in the nucleocapsid (N) protein are associated with higher viral loads in COVID-19 patients. Our comparative biochemical analysis reveals that the mutant N protein displays enhanced viral RNA binding and differential interaction with key host proteins. We found increased interaction of GSK3A kinase simultaneously with hyper-phosphorylation of the adjacent serine site (S206) in the mutant N protein. Furthermore, the host cell transcriptome analysis suggests that the mutant N protein produces dysregulated interferon response genes. Here, we provide crucial information in linking the R203K/G204R mutations in the N protein to modulations of host-virus interactions and underline the potential of the nucleocapsid protein as a drug target during infection.
Subject(s)
COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Genome, Viral , Mutation, Missense , SARS-CoV-2/genetics , COVID-19/enzymology , COVID-19/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Host-Pathogen Interactions , Humans , Nucleocapsid/genetics , Nucleocapsid/metabolism , Phosphorylation , Phylogeny , Protein Binding , SARS-CoV-2/classification , SARS-CoV-2/physiology , Saudi Arabia , Viral Load , Virus ReplicationABSTRACT
OBJECTIVES: Stress-induced peptic ulcer disease (SPUD) refers to erosions in the mucosa of the upper gastrointestinal tract that are caused by stress. Some antidepressants are reported to have antioxidant and antiulcer effects. However, histopathological and biochemical evaluation of the anti-ulcer activity of a comparable antidepressant, fluvoxamine, has not been adequately investigated. This study aims to determine the anti-ulcer efficacy of fluvoxamine in reducing stress-induced histopathological and biochemical changes in the gastric mucosa. METHODS: Thirty adult male albino rats were divided into three groups of 10 rats each: the control groups, the SPUD group, and the fluvoxamine-pre-treated group, which received fluvoxamine for eight days before stress exposure. The cold-restraint stress method was used to induce stomach ulcers in the SPUD and fluvoxamine groups. Afterward, the stomachs of rats were removed, opened, and ulcer indices were calculated. Light microscopy was performed following haematoxylin and eosin staining, periodic acid Schiff's, Masson's trichrome staining, and proliferating cell nuclear antigen immunostaining. Gastric tissue levels of oxidative stress markers were measured and compared among groups. RESULTS: The stomachs of the fluvoxamine-treated rats showed a significantly lower number of ulcers with minimal mucosal injury compared with those of rats from the SPUD group. The oxidative stress marker levels and SPUD ulcer indices were significantly different among groups. CONCLUSION: Fluvoxamine pre-treatment exerted a gastroprotective effect against ulcer development and promoted healing of the developed lesions.
