Effect of DAMP HMGB -1 and RAGE receptor on endothelial transmigration of monocytes infected by Zika virus

• Grant number: 16/08061-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2016
• End date: September 30, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alberto José da Silva Duarte
• Grantee: Gabriel Costa de Carvalho
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 17/22539-0 - Effect of DAMP HMGB -1 and RAGE receptor on endothelial transmigration of monocytes infected by Zika virus, BE.EP.PD

Abstract

Zika is a disease caused by a zika virus (ZKV) transmitted by Aedes aegypti mosquitoes, which also transmit dengue and chikungunya. The ZKV is able to reach the placenta, amniotic fluid and may cause neurological abnormalities such as fetal microcephaly, but the mechanisms remain to be elucidated. Various factors such as danger associated molecular pattern (DAMP) as the HMGB-1 (High mobility group box 1 protein) and heat shock proteins Hsp90 and Hsp70, are produced in viral inflammatory response, and may enhance antiviral response. In the case of flavivirus, which are neurotropics, some viral components may contribute to the viral spread by altering the permeability of endothelial cells or increase their proliferative potential, making it allowable to infection. The main objective of this project is to evaluate the influence of HMGB1 in the advanced glycation receptor (RAGE) of newborns and adults monocytes, in the in vitro infection by ZKV or by the action of nonstructural protein 1 (NS1) of ZKV. The HMGB-1 may contribute to breakdown of endothelial homeostasis and facility of the vascular permeability, thus we will investigate the effect of HMGB-1/RAGE in umbilical cord endothelial cell lines (HUVEC) and brain microvascular endothelial cells (HCMEC/D3) in vitro, and the degree of dissociation of cadherins and the actin fibers will be examined by confocal microscopy. The involvement of HMGB1/RAGE will also be assessed in antiviral and inflammatory response of monocytes, as well as the supporting action of Hsp70 and Hsp90 on the activation of monocytes infected by ZKV PCRarray, which will be investigated using the kit Interferons and Receptors RT2 Profiler. The HMGB1 action mechanisms in endothelial transmigration of monocytes infected by ZKV will be investigated by transwell assay and the release of chemokines measured by flow cytometry. The use of anti-HMGB 1 monoclonal antibodies will be used to block the interaction HMGB-1/RAGE will be used to analyze decreased inflammatory response and viral replication. However, understanding the process of pathogenesis and dissemination of ZKV can provide important data on the outline of infection control strategies, particularly for regulation of DAMP HMGB-1 in fetal/neonatal period.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE CARVALHO, GABRIEL COSTA; BORGET, MARIE-YOLANDE; BERNIER, STEPHANE; GARNEAU, DANIEL; DA SILVA DUARTE, ALBERTO JOSE; DUMAIS, NANCY. RAGE and CCR7 mediate the transmigration of Zika-infected monocytes through the blood-brain barrier. Immunobiology, v. 224, n. 6, p. 792-803, NOV 2019. (17/22539-0, 16/08061-7)