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: 24/02163-9
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Agreement: CNPq
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Luis Lamberti Pinto da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 19/26119-0 - Emerging and re-emerging viruses: biology, pathogenesis and prospection, AP.TEM
• Associated scholarship(s): 24/11175-0 - Study of the mechanisms of assembly and budding of the arboviruses Oropouche and Zika in neurons and the effects of infection on neuronal proteostasis., BP.JD

Abstract

The Zika virus (ZIKV) and the Oropouche virus (OROV) are emerging arboviruses of great importance to public health, and due to global climate changes, they have the potential to spread to new tropical and subtropical regions. While ZIKV caused a severe epidemic in Brazil, OROV causes recurrent and recent outbreaks in the Caribbean and tropical regions of Latin America. Both viruses, despite belonging to distinct viral families, exhibit neurotropism, causing neurological damage in infected individuals. ZIKV is associated with congenital anomalies such as microcephaly, Guillain-Barré Syndrome, transverse myelitis, and meningoencephalitis, while OROV infection can progress to encephalitis or aseptic meningitis. Considering the unique characteristics of the neuronal cells involved in these pathologies, it is crucial to understand how the replicative cycle and viral assembly/budding are regulated in neurons and which host proteins are involved in these processes. In this sense, both Orthoflaviviruses 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 the processing of the amyloid precursor protein (APP) that generates neurotoxic peptides and in the function of the epidermal growth factor receptor (EGFR). Therefore, we will investigate the importance of the ESCRT machinery in the replication and budding of ZIKV and OROV in neurons, identifying which viral proteins are responsible for their subversion. Additionally, we will examine the consequences of ESCRT machinery hijacking by these viruses on cellular proteostasis, involving the trafficking and processing of APP and EGFR. These results will contribute to the understanding of the dynamics of ZIKV and OROV infection in the central nervous system. By identifying targets and molecular pathways of ZIKV and OROV infection, our work will provide valuable insights for pharmacological exploration and potential therapeutic interventions. (AU)