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

Grant number: 17/22539-0
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 12, 2018
Effective date (End): March 11, 2019
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Alberto José da Silva Duarte
Grantee:Gabriel Costa de Carvalho
Supervisor abroad: Nancy Dumais
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Université de Sherbrooke (UdeS), Canada  
Associated to the scholarship:16/08061-7 - Effect of DAMP HMGB -1 and RAGE receptor on endothelial transmigration of monocytes infected by Zika virus, BP.PD


Zika virus (ZIKV) is a flavivirus transmitted by Aedes sp. and Culex sp. mosquitoes, is capable to infect human and has association with neurological disorders such as fetal microcephaly and Guillain-Barré syndrome. Monocytes are important innate immune cells that are infected by flaviviruses, have ability to transmigrate through endothelial barriers in response to CCL2. Considering that pathogen associated molecular patterns - PAMPs, such as lipopolysaccharide (LPS) and danger-associated molecular patterns - DAMPs, such as HMGB1 protein, are factor that could be present during an infection course and can lead to the dissociation of endothelia, It is essential to understand how viruses can transmigrate barriers via a "trojan horse". The HMGB-1 when bind to RAGE (receptor for advanced glycation end-products) is capable to induce an inflammatory cellular profile and when elevated in serum is associated with aggravation of various viral infections. However, the contribution of PAMPs and DAMPs in ZIKV infection and the system in who cells transmigrate through endothelial barriers is unknown. The main objective of this project is to evaluate the effect of HMGB-1 on monocyte infection by Zika virus and on cell transmigration through the cerebral endothelium. The HMGB-1 is able to contribute to the breakdown of endothelial homeostasis and facilitate vascular permeability. In this way, the effect of HMGB-1 / RAGE on brain microvasculature cells (BMEC) in vitro will be investigated, and the degree of dissociation will be performed by endothelial resistance assay (TEER). The HMGB1 / RAGE participation will be evaluated in during the ZKV monocytes infection. This will be achieved by detection of factors such as TNF-alfa, IL1-beta, IL-6, IFN-gama and IFN-alfa. The mechanism of action of HMGB1 on the endothelial transmigration of monocytes infected by ZKV will be investigated using the transwell migration system and the production of chemokines CCL2, CCL3 and CCL4 determined by flow cytometry. The Blockage of HMGB1 / RAGE interaction by anti-HMGB-1 monoclonal antibodies it will be used to analyze a possible reduction of inflammatory response, cell migration and viral replication. However, an understanding of the pathogenesis and dissemination process of ZKV can provide important data and can create an infection control strategy, especially for the regulation of HMGB-1 DAMP in the fetal / neonatal period.

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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, . (17/22539-0, 16/08061-7)

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