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.

Scratching the Surface Takes a Toll: Immune Recognition of Viral Proteins by Surface Toll-like Receptors

“…Modhiran et al attribute previous studies observing a role for TLR2/6 potentially as the result of Escherichia coli contaminants present in the NS1 preparation among other variables [ 108 ]. Two additional studies by Aguilar-Briseño et al explored the role of surface TLRs in responding to DENV but did not identify specific proteins [ 110 , 111 ]. These studies examined all DENV serotypes, identifying that all serotypes activate TLR2/6, not TLR1 or TLR4, resulting in the expression and production of canonical inflammatory cytokines including TNF and IL-6 in human PBMCs [ 110 , 111 ].…”

“…Two additional studies by Aguilar-Briseño et al explored the role of surface TLRs in responding to DENV but did not identify specific proteins [ 110 , 111 ]. These studies examined all DENV serotypes, identifying that all serotypes activate TLR2/6, not TLR1 or TLR4, resulting in the expression and production of canonical inflammatory cytokines including TNF and IL-6 in human PBMCs [ 110 , 111 ]. In addition, immature DENV particles, which are non-infectious in the absence of anti-DENV antibody, activated TLR2/6 in human PBMCs suggesting that the innate immune system senses DENV independent of viral replication [ 111 ].…”

“…These studies examined all DENV serotypes, identifying that all serotypes activate TLR2/6, not TLR1 or TLR4, resulting in the expression and production of canonical inflammatory cytokines including TNF and IL-6 in human PBMCs [ 110 , 111 ]. In addition, immature DENV particles, which are non-infectious in the absence of anti-DENV antibody, activated TLR2/6 in human PBMCs suggesting that the innate immune system senses DENV independent of viral replication [ 111 ]. This suggests that in addition to NS1, which is produced post-infection, DENV contains ligands present in the envelope that activate TLR2 ( Figure 4 ).…”