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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.
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http://dx.doi.org/10.1016/j.celrep.2025.116210 | DOI Listing |
Cell Rep
August 2025
Department of Virology, Juntendo University School of Medicine, Tokyo, Japan. Electronic address:
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.
View Article and Find Full Text PDFAntiviral Res
August 2025
Department of Pathogen Biology, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China. Electronic address:
Approximately 390 million individuals globally are infected with dengue virus annually. Notably, no specific therapeutic strategy has been clinically approved for dengue fever to date. In this study, molecular docking screening against the methyltransferase (MTase) domain of the dengue virus (DENV) NS5 protein unveiled hypaphorine as a high-affinity ligand, with calculated binding energies of -6.
View Article and Find Full Text PDFCell Metab
July 2025
MIVEGEC, University Montpellier, IRD, CNRS, Montpellier, France; Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand. Electronic address:
Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses.
View Article and Find Full Text PDFFront Immunol
May 2025
Access to Advanced Health Institute (AAHI), formerly Infectious Disease Research Institute, Seattle, WA, United States.
Introduction: Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases.
View Article and Find Full Text PDFJ Biomed Sci
January 2025
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico.
Mosquito-borne flaviviruses represent a public health challenge due to the high-rate endemic infections, severe clinical outcomes, and the potential risk of emerging global outbreaks. Flavivirus disease pathogenesis converges on cellular factors from vectors and hosts, and their interactions are still unclear. Exosomes and microparticles are extracellular vesicles released from cells that mediate the intercellular communication necessary for maintaining homeostasis; however, they have been shown to be involved in disease establishment and progression.
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