Study of the mechanisms of assembly and budding of the arboviruses Oropouche and Zika in neurons and the effects of infection on neuronal proteostasis.

• Grant number: 24/11175-0
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: July 01, 2024
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Agreement: CNPq
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Roger Luiz Rodrigues
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 24/02163-9 - Study of the mechanisms of assembly and budding of the arboviruses Oropouche and Zika in neurons and the effects of infection on neuronal proteostasis, AP.R

Abstract

The Zika virus (ZIKV) and the Oropouche virus (OROV) are emerging arboviruses of great importance to publichealth, and due to global climate changes, they have the potential to spread to new tropical and subtropicalregions. While ZIKV caused a severe epidemic in Brazil, OROV causes recurrent and recent outbreaks in theCaribbean and tropical regions of Latin America. Both viruses, despite belonging to distinct viral families, exhibitneurotropism, causing neurological damage in infected individuals. ZIKV is associated with congenital anomaliessuch as microcephaly, Guillain-Barré Syndrome, transverse myelitis, and meningoencephalitis, while OROVinfection can progress to encephalitis or aseptic meningitis. Considering the unique characteristics of the neuronalcells involved in these pathologies, it is crucial to understand how the replicative cycle and viral assembly/buddingare regulated in neurons and which host proteins are involved in these processes. In this sense, bothOrthoflaviviruses and Orthobunyaviruses utilize the host cell's ESCRT machinery for their replication and budding.The ESCRT machinery is important in regulating endocytic pathways and cellular proteostasis, participating in theprocessing of the amyloid precursor protein (APP) that generates neurotoxic peptides and in the function of theepidermal growth factor receptor (EGFR). Therefore, we will investigate the importance of the ESCRT machinery inthe replication and budding of ZIKV and OROV in neurons, identifying which viral proteins are responsible for theirsubversion. Additionally, we will examine the consequences of ESCRT machinery hijacking by these viruses oncellular proteostasis, involving the trafficking and processing of APP and EGFR. These results will contribute to theunderstanding of the dynamics of ZIKV and OROV infection in the central nervous system. By identifying targetsand molecular pathways of ZIKV and OROV infection, our work will provide valuable insights for pharmacologicalexploration and potential therapeutic interventions. (AU)