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<p>Antibody-dependent enhancement (ADE) of dengue virus-type 2 (DENV2) is a major risk factor for severe disease, facilitating Fcγ receptor–mediated viral entry and triggering inflammation that compromises vascular integrity. While Toll-like receptor 2 (TLR2) on monocytes promotes DENV2, strain 16681 infection in these cells and triggers an inflammatory response that activates the endothelium, its contribution to ADE remains unclear. Here, using peripheral blood mononuclear cells, we compared FcγRII (CD32)-mediated ADE infection with direct infection and assessed the contributions of TLR2, RNA sensors (TLR8, TLR3), and spleen tyrosine kinase (SYK). Blocking CD32 or SYK reduced antibody-enhanced infection to direct infection levels, whereas TLR2 inhibition abolished infection entirely. Furthermore, TLR8, TLR3, and SYK mediated inflammatory responses under both ADE and direct infection. These findings identify TLR2 as indispensable also for CD32/SYK-driven viral entry and implicate TLR8, TLR3, and SYK in ADE-associated inflammation. Our study provides mechanistic insight into ADE pathogenesis and highlights potential targets for mitigating severe dengue outcomes.</p>

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The contributions of TLR2, TLR8 and TLR3 to direct and antibody-dependent enhancement of dengue virus serotype 2 infection

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月17日

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  • B. M. ter Ellen,
  • M. Punekar,
  • J. A. Castillo,
  • J. F. Valdés-López,
  • V. Upasani,
  • S. Sann,
  • M. Karnthaler,
  • B. Martija,
  • J. Moser,
  • J. M. Smit,
  • T. Cantaert,
  • I. A. Rodenhuis-Zybert

摘要

Antibody-dependent enhancement (ADE) of dengue virus-type 2 (DENV2) is a major risk factor for severe disease, facilitating Fcγ receptor–mediated viral entry and triggering inflammation that compromises vascular integrity. While Toll-like receptor 2 (TLR2) on monocytes promotes DENV2, strain 16681 infection in these cells and triggers an inflammatory response that activates the endothelium, its contribution to ADE remains unclear. Here, using peripheral blood mononuclear cells, we compared FcγRII (CD32)-mediated ADE infection with direct infection and assessed the contributions of TLR2, RNA sensors (TLR8, TLR3), and spleen tyrosine kinase (SYK). Blocking CD32 or SYK reduced antibody-enhanced infection to direct infection levels, whereas TLR2 inhibition abolished infection entirely. Furthermore, TLR8, TLR3, and SYK mediated inflammatory responses under both ADE and direct infection. These findings identify TLR2 as indispensable also for CD32/SYK-driven viral entry and implicate TLR8, TLR3, and SYK in ADE-associated inflammation. Our study provides mechanistic insight into ADE pathogenesis and highlights potential targets for mitigating severe dengue outcomes.