The role of emerging and reemerging virus infections in the activation of latent viral elements and their possible impacts on neuroinflammation and neurodegeneration.

• Grant number: 24/19558-6
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Juliana Terzi Maricato
• Grantee: Juliana Terzi Maricato
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexandre Salgado Basso ; Daniela Santoro Rosa ; José Luiz Proença Módena ; Marimélia Aparecida Porcionatto ; Nilmar Silvio Moretti

Abstract

Increasing evidence points to a relationship between viral infections (chronic or acute) and the development of neurological alterations, neurocognitive and neurodegenerative diseases. Recent examples include: the reactivation of human endogenous herpesviruses and retroviruses and the development of encephalitis, dementia and multiple sclerosis; arbovirus infection and the development of microcephaly, paralysis and other neurodegenerative diseases; and the neurological sequelae after COVID-19. These findings lead us to speculate that different viral elements acting together may induce neuroinflammation and neurodegeneration, which would impair the homeostasis of the blood-brain barrier (BBB) and the central nervous system (CNS), leading to the development of neurological sequelae or dysfunctions. Thus, the present project aims to study the role of infections by emerging and reemerging viruses (SARS-CoV-2, DENV and OROV) in the activation of latent viral elements (HHV-1, HHV-3 and HERVs) and their possible impacts on neuroinflammation and neurodegeneration. From human neuronal lines infected with latent HHV-1 or HHV-3 generated in our laboratory, the following in vitro models will be used for infection with different emerging and reemerging viruses (SARS-CoV-2, DENV or OROV): (i) monocultures of the generated neurons; (ii) cocultures of human astrocytes with the generated neurons; (iii) cocultures of human microglia with the generated neurons and (iv) a transwell BBB model composed of endothelial cells, microglia, human astrocytes and the generated neurons. In these models, after infection by SARS-CoV-2, DENV or OROV viruses, the following aspects will be evaluated and correlated: (i) the possible reactivation of HHV-1 and HHV-3; (ii) the expression profile of HERVs; (iii) inflammatory, immunological and epigenetic parameters and viral load; (iv) parameters related to neurotoxicity, BBB integrity and permeability and neurodegeneration. Furthermore, we aim to identify factors and mechanisms that mediate the observed effects, which will enable a better understanding of the mechanisms by which different viral elements together can impact neuroinflammatory and neurodegenerative processes. The results are expected to have a significant impact on public health, especially in the development of new preventive and therapeutic approaches for diseases caused by emerging and re-emerging viruses and for neurodegenerative diseases. (AU)