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Tissue-molecular alterations associated with viral infections in adult human brain slice cultures

Grant number: 21/12263-2
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2022
Effective date (End): March 01, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Adriano Silva Sebollela
Grantee:Glaucia Maria de Almeida
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):23/01202-8 - Subcellular localization of Oropouche virus in human brain slice cultures using super-resolution microscopy, BE.EP.DR

Abstract

Neurotropic viruses can cause central nervous system (CNS) diseases. About 30% of confirmed encephalitis cases are attributed to viral infections. Despite that, the molecular mechanisms and cellular alterations resulting from viruses infections in the human brain are still not well characterized. Murine models have been widely used to elucidate mechanisms associated with viral infections, however, significant biochemical and functional differences between rodent and human brains limit their application as a translational model. Recently, human brain organoids have emerged as an important tool for the study of viral neuropathologies. However, brain organoids still have important limitations, such as the lack of a mature cortical architecture and the complex network of interactions between neurons and glial cells. In this context, adult human brain tissue cultures become a powerful tool, as the cytoarchitecture and cell connections are preserved. In this project, we propose to evaluate the neurotropic potential of Oropouche (OROV), Zika (ZIKV) and SARS-CoV-2 viruses, as well as to understand the tissue-molecular impacts that direct infection by these viruses can have on the adult human CNS, in a model of adult human brain slices. We will evaluate the susceptibility and permissiveness of human brain slices to infections by these viruses, and we will identify and quantify the neuropathological and molecular alterations resulting from these infections, such as tissue morphology, release of cytokines and neurotransmitters, cell activation markers (microgliosis and astrogliosis), markers of neuronal and synaptic damage, cell death, mitochondrial metabolism and proteomics. We hope that this project will significantly contribute to our understanding of the consequences for the adult human brain of OROV, ZIKV and SARS-CoV-2 infections. And we believe that, in the future, new treatments for these consequences arising from the knowledge generated in this Project can be developed.

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