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

  • Npj Viruses. 2026 Apr 17;4(1):24. doi: 10.1038/s44298-026-00190-9.
B M Ter Ellen  1 ,  M Punekar  #  1 ,  J A Castillo  #  1 ,  J F Valdés-López  1 ,  V Upasani  1 ,  S Sann  2 ,  M Karnthaler  1 ,  B Martija  1 ,  J Moser  3 ,  J M Smit  1 ,  T Cantaert  2 ,  I A Rodenhuis-Zybert  4
Affiliations
  • 1. Department of Medical Microbiology and Infection Prevention, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • 2. Immunology Unit, Institut Pasteur du Cambodge, Pasteur Network, Phnom Penh, Cambodia.
  • 3. Departments of Critical Care, Pathology & Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 4. Department of Medical Microbiology and Infection Prevention, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 41998173 DOI: 10.1038/s44298-026-00190-9
Abstract

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.

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