TLR2 axis on peripheral blood mononuclear cells regulates inflammatory responses to non-infectious immature dengue virus particles.

Abstract

Severe dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection.

• Authors: José Alberto Aguilar Briseño, Lennon Ramos Pereira, Marleen van der Laan, Mindaugas Pauzuolis, Bram M Ter Ellen, Vinit Upasani, Jill Moser, Luís Carlos de Souza Ferreira, Jolanda M Smit, Izabela A Rodenhuis-Zybert
• Journal: PLoS pathogens (PLoS Pathog) Vol. 18 Issue 10 Pg. e1010499 (10 2022) ISSN: 1553-7374 [Electronic] United States
• PMID: 36240261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Toll-Like Receptor 2
• Toll-Like Receptor 6
• Tumor Necrosis Factor-alpha
• NF-kappa B
• TLR2 protein, human

Topics

• Humans
• Toll-Like Receptor 2
• Dengue Virus
• Leukocytes, Mononuclear
• Toll-Like Receptor 6
• Tumor Necrosis Factor-alpha
• NF-kappa B
• Inflammation
• Dengue
• Virion