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About the Authors:
Dustin R. Glasner
Roles Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
ORCID http://orcid.org/0000-0001-9821-6683
Kalani Ratnasiri
Roles Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review & editing
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
ORCID http://orcid.org/0000-0001-5953-0004
Henry Puerta-Guardo
Roles Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
ORCID http://orcid.org/0000-0003-3050-4480
Diego A. Espinosa
Roles Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - review & editing
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
ORCID http://orcid.org/0000-0002-4364-5031
P. Robert Beatty
Roles Conceptualization, Supervision, Writing - original draft, Writing - review & editing
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
Eva Harris
Roles Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
* E-mail: [email protected]
Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States of America
ORCID http://orcid.org/0000-0002-7238-4037Abstract
Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examined the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely-related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-[alpha] , IL-6, IL-8) and that blocking these...