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Published: October 14, 2022
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
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.
Author summary
We have previously demonstrated that Toll-like receptor 2 (TLR2), present on the surface of human monocytes, can sense DENV infection leading to the production of soluble inflammatory mediators and the activation of the endothelium. Interestingly, a large proportion of DENV particles released from the infected cells are not readily infectious because they did not complete the maturation process. Here we aimed to elucidate if and how these non-infectious, immature DENV particles contribute to systemic inflammation. We evaluated if monocytes sense immature DENV and found that sensing of immature DENV induced early inflammatory responses in PBMCs. Subsequently, by pharmacological inhibition of TLR2 and pathways downstream we demonstrated that TLR2 and CD14 drive the early production inflammatory mediators and endothelial activation. Importantly however, prolonged inhibition of TLR2 induced a second wave of TNF-α release and the subsequent activation of the endothelium. Taken together, our study showed that although virtually non-infectious, immature DENV particles can contribute to inflammatory responses and that TLR2 play an important role in their initiation and resolution. We propose that the maturation status of DENV in the human host can influence the extent and kinetics of the inflammatory responses during DENV infection.
Published: October 14, 2022
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
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.
Author summary
We have previously demonstrated that Toll-like receptor 2 (TLR2), present on the surface of human monocytes, can sense DENV infection leading to the production of soluble inflammatory mediators and the activation of the endothelium. Interestingly, a large proportion of DENV particles released from the infected cells are not readily infectious because they did not complete the maturation process. Here we aimed to elucidate if and how these non-infectious, immature DENV particles contribute to systemic inflammation. We evaluated if monocytes sense immature DENV and found that sensing of immature DENV induced early inflammatory responses in PBMCs. Subsequently, by pharmacological inhibition of TLR2 and pathways downstream we demonstrated that TLR2 and CD14 drive the early production inflammatory mediators and endothelial activation. Importantly however, prolonged inhibition of TLR2 induced a second wave of TNF-α release and the subsequent activation of the endothelium. Taken together, our study showed that although virtually non-infectious, immature DENV particles can contribute to inflammatory responses and that TLR2 play an important role in their initiation and resolution. We propose that the maturation status of DENV in the human host can influence the extent and kinetics of the inflammatory responses during DENV infection.