TLR2 on blood monocytes senses dengue virus infection and its expression correlates with disease pathogenesis

• Published in: Nature communications 2020-06, Vol.11 (1), p.3177-3177, Article 3177
• Main Authors: Aguilar-Briseño, José A., Upasani, Vinit, Ellen, Bram M. ter, Moser, Jill, Pauzuolis, Mindaugas, Ruiz-Silva, Mariana, Heng, Sothy, Laurent, Denis, Choeung, Rithy, Dussart, Philippe, Cantaert, Tineke, Smit, Jolanda M., Rodenhuis-Zybert, Izabela A.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/21; 13/31; 38/77; 631/250/2504; 631/250/255/2514; 631/326/596; 631/326/596/1413; Blocking; Blood; Capillary Permeability; CD14 antigen; Cell activation; Chemokines; Chemokines - metabolism; Child; Child, Preschool; Correlation; Cytokines; Cytokines - metabolism; Dengue; Dengue - immunology; Dengue - virology; Dengue fever; Dengue hemorrhagic fever; Dengue Virus; Dengue Virus - metabolism; Endothelium; Endothelium, Vascular; Endothelium, Vascular - metabolism; Female; Gene Expression Regulation; GPI-Linked Proteins; GPI-Linked Proteins - metabolism; Humanities and Social Sciences; Humans; Immunity, Innate; Immunology; Infections; Inflammation; Integrity; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Life Sciences; Lipopolysaccharide Receptors; Lipopolysaccharide Receptors - metabolism; Male; Microbiology and Parasitology; Monocytes; Monocytes - metabolism; multidisciplinary; NF-kappa B; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Pediatrics; Peripheral blood mononuclear cells; Permeability; Receptors; Receptors, IgG; Receptors, IgG - metabolism; Science; Science (multidisciplinary); Severity of Illness Index; TLR2 protein; Toll-Like Receptor 2; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 6; Toll-like receptors; Vector-borne diseases; Virology; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16849-7

Vascular permeability and plasma leakage are immune-pathologies of severe dengue virus (DENV) infection, but the mechanisms underlying the exacerbated inflammation during DENV pathogenesis are unclear. Here, we demonstrate that TLR2, together with its co-receptors CD14 and TLR6, is an innate sensor of DENV particles inducing inflammatory cytokine expression and impairing vascular integrity in vitro. Blocking TLR2 prior to DENV infection in vitro abrogates NF-κB activation while CD14 and TLR6 block has a moderate effect. Moreover, TLR2 block prior to DENV infection of peripheral blood mononuclear cells prevents activation of human vascular endothelium, suggesting a potential role of the TLR2-responses in vascular integrity. TLR2 expression on CD14 + + classical monocytes isolated in an acute phase from DENV-infected pediatric patients correlates with severe disease development. Altogether, these data identify a role for TLR2 in DENV infection and provide insights into the complex interaction between the virus and innate receptors that may underlie disease pathogenesis. The mechanisms underlying immunpathologies in dengue virus (DENV) infection are incompletely understood. Here, authors show that TLR2 recognizes DENV particles inducing cytokine expression and activating vascular endothelium cells in vitro, and that TLR2 expression on monocytes correlates with disease severity in patients.