Selective TLR ligand stimulation enhances in vivo mosquito-borne flavivirus pathogenicity
Mosquito saliva facilitates pathogen transmission and enhances the severity of diseases caused by mosquito-borne viruses; however, the underlying mechanisms are unknown. Here, we demonstrate that mosquito salivary gland extracts (SGEs) enhance flaviviral pathogenicity in vivo by activating innate immune responses following the accumulation of immune cells at the infection site. Among the innate immune signaling pathways, the TLR2 pathway enhances flaviviral pathogenicity in a manner similar to that of SGEs. TLR2 ligands and SGEs induce neutrophils to secrete chemokines that recruit virus-permissive monocytes and macrophages to infection sites. SGEs activate TLR2, and inhibition of TLR2 signaling markedly reduces mosquito-saliva-enhanced viral pathogenicity. Overall, this study provides important insights into vector-host interactions and suggests that TLR2 is a potential target for preventing mosquito-borne flaviviral infection.
Authors
- Daisuke Okuzaki (ORCID: https://orcid.org/0000-0002-4552-783X)
- Ronald Enrique Morales Vargas (ORCID: https://orcid.org/0000-0002-8013-5372)
- Tomomi Hishinuma (ORCID: https://orcid.org/0009-0003-7528-8002)
- Takeshi Kurosu (ORCID: https://orcid.org/0000-0002-4648-6419)
- Hirofumi Sawa (ORCID: https://orcid.org/0000-0003-2569-2755)
- Yusuke Sakai (ORCID: https://orcid.org/0000-0001-8810-4813)
- Yasuko Orba (ORCID: https://orcid.org/0000-0001-9910-3912)
- Chang‐Kweng Lim (ORCID: https://orcid.org/0000-0001-5823-8300)
- Yumi Itoh (ORCID: https://orcid.org/0000-0001-5501-3413)
- Masayuki Saijo (ORCID: https://orcid.org/0000-0001-5458-7298)
- Takashi Satoh (ORCID: https://orcid.org/0000-0002-6064-9253)
- Yuki Eshita (ORCID: https://orcid.org/0000-0002-1468-703X)
- Tatsuya Suzuki (ORCID: https://orcid.org/0000-0002-9265-900X)
- Shigeru Tajima (ORCID: https://orcid.org/0000-0002-1981-9062)
- Atsushi Yamanaka (ORCID: https://orcid.org/0000-0002-2757-2792)
- Thipruethai Phanitchat
- Toru Okamoto (ORCID: https://orcid.org/0000-0003-4000-3102)
- Tsukika Tanaka
- Shizuo Akira
- Yuka Miyata
- Yoshiharu Matsuura
- Saori Haga
Institutions
- Tokyo Medical and Dental University (JP)
- Hokkaido University (JP)
- Mahidol University (TH)
- Sapporo International University (JP)
- Juntendo University (JP)
- National Institute of Infectious Diseases (JP)
- Mahidol Oxford Tropical Medicine Research Unit (TH)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1016/j.celrep.2025.116210
- Citations
- 4
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 7.51
Funders
- Japan Agency for Medical Research and Development
- Research Promotion Foundation
- Fondation pour la Recherche Médicale
- Shionogi
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- ACT-X