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The role of innate recognition pathways and type I and III interferons for maintenance of the blood-placental barrier after Oropouche virus infection

Grant number: 21/10615-9
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 01, 2022
Effective date (End): January 31, 2023
Field of knowledge:Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
Principal researcher:José Luiz Proença Módena
Grantee:Stefanie Primon Muraro
Supervisor abroad: Michael S Diamond
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: University of Washington, United States  
Associated to the scholarship:18/13645-3 - The role of innate recognition pathways and type I and III interferons in the rupture of the placental barrier after OROV infection, BP.DR

Abstract

The Oropouche virus (OROV) is an arbovirus with potential to cause epidemics in the most populated regions of Brazil. Individuals infected with OROV develop a febrile illness, which can progress to neurological and hemorrhagic complications. Furthermore, an increased incidence of abortion was reported during major OROV epidemics. However, the pathogenetic mechanisms associated with the hematoplacental barrier breakdown during OROV infection have not yet been investigated. For this, we infected WT, SJL, IFNAR-/- and MAVs-/- mice, explants of placentas and trophoblasts cell lines with OROV in order to characterize the routes of signaling and antiviral response induced by this infection in villous and extravilous trophoblasts. We verified that OROV infection leads to the activation of receptors capable of recognizing the viral genome and induces the expression of type I and III IFNs. In addition, embryos and placenta from OROV-infected mice on the embrionary day (E) 10 showed signals of viral infection and immune activation when they were euthanatized on E16.5, particularly pronounced in IFNAR-/- animals. In fact, we found high levels of IFN± with ISGs activation (OASL and IFIT1) in these mice. Finally, to examine possible abnormalities in the placenta that would lead to damage of the fetus we analyzed glycolytic genes that are present in hypoxia. We found high levels of both PKM2 and PFKFB3 enzymes on the placenta of the IFNAR-/- mice. Genes such as Glut1, Hif1± and IL1² were also overexpressed on the placenta of infected animals. With that we intend to investigate if type III IFN can also be a determinant in the pathogenesis of the placenta by using IL28R-/- mice and if there is an IFN±-independent pathway production by an alternative receptor responsible for the antiviral response to OROV.

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