Analysis of endoproteinases and viral proteinases substrates influencing host metabolic and immunological tolerance in COVID-19: proteomics and degradomics approaches

• Grant number: 22/14928-4
• Support Opportunities: Scholarships abroad - Research
• Start date: July 23, 2023
• End date: July 22, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Arterio Sorgi
• Grantee: Carlos Arterio Sorgi
• Host Investigator: Christopher Overall
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of British Columbia, Vancouver (UBC), Canada

Abstract

Many individuals infected with the severe acute respiratory syndrome virus coronavirus-2 (SARS-CoV-2) develop only mild symptoms, but some could develop a spectrum of severe symptoms. Although little understanding of the immunopathology of SARS-CoV-2, it is well described that this mechanism was associated with hyperinflammation, tissue damage and disruption of host target organ metabolism. Thus, experimental evidence has shown that these processes can also be regulated by endoproteinases (particularly matrix metalloproteinases - MMPs) and viral proteases, such as 3CLpro from SARS-CoV-2; which are important pharmacological targets and may have consequences in the regulation of host cell proteins, being associated with the virus pathogenicity mechanisms. The proteomic approach has allowed large-scale studies of protein expression in different tissues and body fluids. The recent progress of these methodologies, such as degradomics, allowed obtaining more information about possible substrates of proteases, as well as evaluating the primary specificity of these enzymes. Thus, the Terminal Amine Isobaric Labeling Substrate (TAILS) technique has already been employed to identify new viral protease cleavage sites in a lung proteome library. In this project, we aim to demonstrate the role of MMPs and 3CLpro in the regulation of metabolic pathway proteins, cell signaling and immune system mediators in lung epithelial cells infected with SARS-CoV-2. Thus, we suggest a mechanism by which proteases can influence energy metabolism and cell signaling in target organs, such as the lung, and the suitability of these enzymes as therapeutic targets to increase the host's metabolic tolerance to the damage inflicted by COVID-19. (AU)