A TLR2-associated entry pathway promotes productive dengue virus serotype 2 infection and inflammatory responses in classical monocytes
- 1University Medical Center Groningen
Abstract
Severe dengue is characterized by systemic inflammation and vascular leakage. Recent evidence indicates that Toll-like receptor 2 (TLR2) supports early steps of dengue virus (DENV) infection in monocytes, whereas intracellular viral RNA sensing drives much of the subsequent inflammatory response. However, whether this entry-associated function of TLR2 differs among human monocyte subsets remains unknown. Here, we investigated how the TLR2 axis regulates DENV serotype 2 (DENV2) infection and inflammatory output in purified primary human monocytes and sorted monocyte subsets. Blocking TLR2 at the cell surface or targeting its intracellular TIR domain reduced virus-cell association, productive infection, and the release of inflammatory and antiviral mediators. Among TLR2-associated receptors, CD14 and, to a lesser extent, CD36 contributed to efficient infection, whereas TLR1, TLR6, and TLR10 were dispensable under the conditions tested. Notably, TLR2 blockade reduced viral production and cytokine release in CD16- classical monocytes but not in pooled CD16+ monocytes, identifying a subset-specific dependence on the TLR2 axis. TLR3 contributed to inflammatory and antiviral responses without affecting viral replication, consistent with post-entry recognition of viral RNA. Finally, blocking the TLR2 axis during monocyte infection prevented the loss of endothelial barrier integrity induced by monocyte-derived soluble mediators. Together, these findings identify a TLR2-associated entry route that preferentially supports productive DENV2 infection in classical monocytes and thereby enables RNA-sensor-dependent inflammatory responses that compromise endothelial function.
Related
- Arbidol HCl Inhibits PRRSV Infection by Downregulating CD163 and MYH9 Expression and Modulating Inflammatory Responses
- E3 ubiquitin ligase Smurf1 facilitates bacterial infection and regulates inflammatory responses via promoting MyD88 degradation in teleost
- Antibody-opsonized extracellular traps modulate macrophage responses and attenuate their T cell-associated inflammatory and costimulatory characteristics
- Fluoropyrimidine-associated gastrointestinal toxicity: pharmacovigilance reporting signals and in vitro evidence of epithelial injury, barrier impairment, and inflammatory responses
- Glyoxalase 1 (GLO1) Deficiency Is Associated with Myeloid Skewing and Altered Inflammatory Responses.
BibTeX
@misc{castillo2026tlr2associated,
title = {{A TLR2-associated entry pathway promotes productive dengue virus serotype 2 infection and inflammatory responses in classical monocytes}},
author = {J. A. Castillo and M. Punekar and V. Upasani and P. van Duinkerken and B. ter Ellen and H. van der Ende-Metselaar and S. Urcuqui-Inchima and J. M. Smit and I. A. Rodenhuis-Zybert},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755835},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755835v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A TLR2-associated entry pathway promotes productive dengue virus serotype 2 infection and inflammatory responses in classical monocytes
AU - J. A. Castillo
AU - M. Punekar
AU - V. Upasani
AU - P. van Duinkerken
AU - B. ter Ellen
AU - H. van der Ende-Metselaar
AU - S. Urcuqui-Inchima
AU - J. M. Smit
AU - I. A. Rodenhuis-Zybert
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755835
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755835v1
AB - Severe dengue is characterized by systemic inflammation and vascular leakage. Recent evidence indicates that Toll-like receptor 2 (TLR2) supports early steps of dengue virus (DENV) infection in monocytes, whereas intracellular viral RNA sensing drives much of the subsequent inflammatory response. However, whether this entry-associated function of TLR2 differs among human monocyte subsets remains unknown. Here, we investigated how the TLR2 axis regulates DENV serotype 2 (DENV2) infection and inflammatory output in purified primary human monocytes and sorted monocyte subsets. Blocking TLR2 at the cell surface or targeting its intracellular TIR domain reduced virus-cell association, productive infection, and the release of inflammatory and antiviral mediators. Among TLR2-associated receptors, CD14 and, to a lesser extent, CD36 contributed to efficient infection, whereas TLR1, TLR6, and TLR10 were dispensable under the conditions tested. Notably, TLR2 blockade reduced viral production and cytokine release in CD16- classical monocytes but not in pooled CD16+ monocytes, identifying a subset-specific dependence on the TLR2 axis. TLR3 contributed to inflammatory and antiviral responses without affecting viral replication, consistent with post-entry recognition of viral RNA. Finally, blocking the TLR2 axis during monocyte infection prevented the loss of endothelial barrier integrity induced by monocyte-derived soluble mediators. Together, these findings identify a TLR2-associated entry route that preferentially supports productive DENV2 infection in classical monocytes and thereby enables RNA-sensor-dependent inflammatory responses that compromise endothelial function.
ER -