Evaluation of the therapeutic role of selective serotonin reuptake inhibitor antidepressants in modulating the inflammatory response and sphingolipid metabolism in SARS-CoV-2 infected macrophages

• Grant number: 23/07776-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): September 01, 2023
• Effective date (End): December 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Carlos Arterio Sorgi
• Grantee: Jonatan Constança Silva de Carvalho
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic, with serious consequences for affected individuals and society as a whole. The biology and infection process of the virus have been intensively studied to gain a better understanding of the molecular basis of virus-host cell interactions. SARS-CoV-2 is known to bind to angiotensin-converting enzyme 2 (ACE2) via its spike protein. During SARS-CoV-2 infection, the virus also affects sphingolipid homeostasis, which may lead to an exacerbated inflammatory response. Sphingosine and ceramide belong to the sphingolipid family and are abundantly present in cell membranes. These lipids have been shown to interfere with the fusion of SARS-CoV-2 viral particles with primary epithelial cells in culture. The mechanisms of action were partially different, as sphingosine blocked, while ceramide facilitated viral entry. Acid sphingomyelinase (ASM) is vital for ceramide generation and functional inhibition of ASM by drugs reduced entry of SARS-CoV-2 into epithelial cells. Additionally, antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) have been studied in COVID-19. These drugs may act by inhibiting ASM, reducing SARS-CoV-2 infection, and decreasing the production of pro-inflammatory cytokines. In this project, in vitro studies will be carried out using macrophages and inactivated SARS-CoV-2 virus to evaluate the effects of antidepressant drugs on sphingolipid metabolism, production and composition of extracellular vesicles (EVs), viral infection and inflammatory response. The mechanisms by which the SSRIs act in the modulation of these processes will be investigated, using mass spectrometry methodologies, aiming to identify the therapeutic potential of these antidepressant drugs in the modulation of the immune and metabolic response. It is hoped that the results of this study will contribute to the advancement of knowledge about the role of sphingolipids in COVID-19 and highlight the importance of antidepressant drugs as potential adjuvant therapeutic agents in inflammation, offering new perspectives for the treatment of viral infectious diseases.