Effect of placental inflammation and the AMPK signaling pathway on Zika and Oropouche virus infecton

• Grant number: 24/22049-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2025
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Notomi Sato
• Grantee: Laura Luiza Moreira da Silva Dias
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Infections caused by the Zika virus (ZIKV) and Oropouche virus (OROV) represent a significant public health challenge, especially during pregnancy, where they can trigger inflammation in placental tissue and impact fetal development. ZIKV, belonging to the Flaviviridae family, is associated with Congenital Zika Syndrome (CZS), which can result in microcephaly, early death, or permanent cognitive deficits. Recently, OROV, an emerging arbovirus from the Peribunyaviridae family that causes Oropouche fever, has been identified as causing cases of fetal death and severe microcephaly. Increasingly, congenital infections require preventive and therapeutic measures. Our proposal is to investigate whether placental inflammation favors viral replication. Considering that activation via LPS can lead to dephosphorylation of the AMPk pathway (adenosine monophosphate-activated protein kinase), which interferes with antiviral activity, this pathway is a target to be explored. Therefore, we will analyze the mechanisms involved in LPS-induced inflammation in placental tissue associated with ZIKV and OROV infections and its interference with AMPk pathway signaling, examining its impact on viral replication and antiviral factors. The following parameters will be evaluated: (i) investigating whether LPS-induced inflammation in placental explants and trophoblastic cells (Bewo cell line) interferes with ZIKV and OROV infection, (ii) AMPk pathway inhibition and its relationship with viral replication and the expression of pro-inflammatory and antiviral factors, and (iii) the influence of the mTOR pathway on the production of antiviral factors. Modulation of the AMPk and mTOR pathways will be analyzed using modulators such as rapamycin and the Sirtuin-1 inducer,resveratrol. Antiviral factors such as IFN-beta, RIG-I, IRF3, MDA5, IFITM1, IFITM3, MX1, and cytokines like TGF-beta, IL-10, IL37, and IL17 will be analyzed in villous explants. This project aims to investigate the AMPk signaling pathway in placental inflammatory response, to understand if it affects the antiviral response and worsens ZIKV and OROV infections during pregnancy. (AU)