MDV-like endogenous viral elements act as immune rheostats in Aedes cells by modulating defensin A-mediated responses to arboviruses
7 affiliations
- 1School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
- 2Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, China
- 3Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Southern Medical University, Guangzhou, Guangdong, China
- 4Laboratory Medicine Centre, Shenzhen Nanshan People's Hospital, Shenzhen, People’s Republic of China
- 5Shenzhen University Medical School, Shenzhen, People’s Republic of China
- 6Center for Disease Control and Prevention of Southern Theater Command, Guangzhou, China
- 7Guangzhou Center for Disease Control and Prevention, Guangzhou, China
Abstract
Mosquito cell lines are essential tools for arbovirus research. Endogenous viral elements (EVEs) are prevalent in mosquito genomes, yet their functional effects on host immune responses remain unclear, potentially complicating experimental interpretations. In this study, we systematically characterized endogenous mosquito densovirus-like elements (EMLs) within the Aedes aegypti Aag2 cell line and found that these endogenous EMLs are transcriptionally active but translationally defective. The silencing of EML transcripts significantly diminished the replication of Zika virus (ZIKV), Japanese encephalitis virus (JEV), and chikungunya virus (CHIKV), while transiently increasing dengue virus 2 (DENV-2), thereby indicating a virus-dependent regulatory mechanism. Mechanistically, RNA sequencing after EML interference, alongside plasmid-based mimic expression, demonstrated that EML transcripts downregulate defensin A, an antimicrobial peptide produced by mosquitoes. Functional assays using synthetic defensin A showed that this peptide differentially regulates arboviral infection. Binding assays and structural modeling further supported its interaction with viral envelope proteins, while stage-restricted infection assays revealed distinct stages of action: defensin A enhanced adsorption of ZIKV, JEV, and CHIKV, but did not promote DENV-2 adsorption or entry, and instead reduced DENV-2 RNA accumulation at the post-entry replication stage. Our findings highlight a previously unrecognized role of densovirus-derived EVEs in mosquito innate immunity, extending their functional scope from the well-established PIWI-interacting RNA-mediated antiviral defense to the regulation of antimicrobial peptide-associated immune pathways. These findings emphasize the necessity of accounting for EVE activity when analyzing data derived from mosquito cell lines, and suggest that related EVE-mediated immune regulation may contribute to arbovirus dynamics in mosquitoes.
IMPORTANCE: Mosquito-borne viruses such as dengue, Zika, Japanese encephalitis, and chikungunya continue to threaten human health worldwide. Laboratory studies often use Aedes aegypti cell lines to investigate how these viruses interact with their mosquito hosts. Here, we show that the genomes of these cells contain endogenous viral elements derived from mosquito densoviruses. Far from being inert fossils, these sequences are transcriptionally active and regulate mosquito immunity by suppressing the antimicrobial peptide defensin A. This immune modulation influences the replication of different arboviruses in opposite ways, enhancing some while restricting others. Our findings reveal that integrated viral elements can shape the outcome of arbovirus infection, with important implications for interpreting mosquito cell culture experiments and for evaluating endogenous viral element-mediated immune regulation in mosquito–virus interactions.
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BibTeX
@article{xiao2026mdvlike,
title = {{MDV-like endogenous viral elements act as immune rheostats in Aedes cells by modulating defensin A-mediated responses to arboviruses}},
author = {Jie Xiao and Tiantian Wei and Hongzheng Lu and Chunyuan Li and Mei Chen and Peiwen Liu and Xiao-Guang Chen and Zetian Lai and Ruiwen Ren and Jinbao Gu},
journal = {mSphere},
year = {2026},
month = sep,
doi = {10.1128/msphere.00520-26},
url = {https://doi.org/10.1128/msphere.00520-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - MDV-like endogenous viral elements act as immune rheostats in Aedes cells by modulating defensin A-mediated responses to arboviruses
AU - Jie Xiao
AU - Tiantian Wei
AU - Hongzheng Lu
AU - Chunyuan Li
AU - Mei Chen
AU - Peiwen Liu
AU - Xiao-Guang Chen
AU - Zetian Lai
AU - Ruiwen Ren
AU - Jinbao Gu
PY - 2026
DA - 2026/09/11
JO - mSphere
DO - 10.1128/msphere.00520-26
UR - https://doi.org/10.1128/msphere.00520-26
AB - Mosquito cell lines are essential tools for arbovirus research. Endogenous viral elements (EVEs) are prevalent in mosquito genomes, yet their functional effects on host immune responses remain unclear, potentially complicating experimental interpretations. In this study, we systematically characterized endogenous mosquito densovirus-like elements (EMLs) within the Aedes aegypti Aag2 cell line and found that these endogenous EMLs are transcriptionally active but translationally defective. The silencing of EML transcripts significantly diminished the replication of Zika virus (ZIKV), Japanese encephalitis virus (JEV), and chikungunya virus (CHIKV), while transiently increasing dengue virus 2 (DENV-2), thereby indicating a virus-dependent regulatory mechanism. Mechanistically, RNA sequencing after EML interference, alongside plasmid-based mimic expression, demonstrated that EML transcripts downregulate defensin A, an antimicrobial peptide produced by mosquitoes. Functional assays using synthetic defensin A showed that this peptide differentially regulates arboviral infection. Binding assays and structural modeling further supported its interaction with viral envelope proteins, while stage-restricted infection assays revealed distinct stages of action: defensin A enhanced adsorption of ZIKV, JEV, and CHIKV, but did not promote DENV-2 adsorption or entry, and instead reduced DENV-2 RNA accumulation at the post-entry replication stage. Our findings highlight a previously unrecognized role of densovirus-derived EVEs in mosquito innate immunity, extending their functional scope from the well-established PIWI-interacting RNA-mediated antiviral defense to the regulation of antimicrobial peptide-associated immune pathways. These findings emphasize the necessity of accounting for EVE activity when analyzing data derived from mosquito cell lines, and suggest that related EVE-mediated immune regulation may contribute to arbovirus dynamics in mosquitoes. IMPORTANCE: Mosquito-borne viruses such as dengue, Zika, Japanese encephalitis, and chikungunya continue to threaten human health worldwide. Laboratory studies often use Aedes aegypti cell lines to investigate how these viruses interact with their mosquito hosts. Here, we show that the genomes of these cells contain endogenous viral elements derived from mosquito densoviruses. Far from being inert fossils, these sequences are transcriptionally active and regulate mosquito immunity by suppressing the antimicrobial peptide defensin A. This immune modulation influences the replication of different arboviruses in opposite ways, enhancing some while restricting others. Our findings reveal that integrated viral elements can shape the outcome of arbovirus infection, with important implications for interpreting mosquito cell culture experiments and for evaluating endogenous viral element-mediated immune regulation in mosquito–virus interactions.
SN - 2379-5042
ER -