JNK pathway restricts DENV2, ZIKV and CHIKV infection by activating complement and apoptosis in mosquito salivary glands

Abstract

Arbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. We also describe a transcriptomic response associated to apoptosis, blood-feeding and lipid metabolism. The three viruses differentially regulate components of Toll, Immune deficiency (IMD) and c-Jun N-terminal Kinase (JNK) pathways. However, silencing of the Toll and IMD pathway components showed variable effects on SG infection by each virus. In contrast, regulation of the JNK pathway produced consistent responses in both SGs and midgut. Infection by the three viruses increased with depletion of the activator Kayak and decreased with depletion of the negative regulator Puckered. Virus-induced JNK pathway regulates the complement factor, Thioester containing protein-20 (TEP20), and the apoptosis activator, Dronc, in SGs. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. Upon infection in SGs, TEP20 induces antimicrobial peptides (AMPs), while Dronc is required for apoptosis independently of TEP20. In conclusion, we revealed the broad antiviral function of JNK pathway in SGs and showed that it is mediated by a TEP20 complement and Dronc-induced apoptosis response. These results expand our understanding of the immune arsenal that blocks arbovirus transmission.

Identification of COVID-19 and Dengue Host Factor Interaction Networks Based on Integrative Bioinformatics Analyses

“…In addition, the findings from a study about JNK by Avisha Chowdhury suggest that the pathways have a broad antiviral function against DENV, depending on apoptosis induction and the complement system. Moreover, activated c-JUN participates in controlling the rearrangement of membrane structures, which is induced by DENV and required for replication ( 49 ).…”

A Thioester-Containing Protein Controls Dengue Virus Infection in Aedes aegypti Through Modulating Immune Response

“…The expression of AMPs is regulated by the AaSR-C/AaMCR complex for potent anti-DENV activity. Additionally, previous studies have also suggested that AMPs play crucial roles in mosquito immune defense against DENV ( 31 – 33 ). Therefore, we hypothesized that TEP1 controls DENV replication by regulating the expression of AMPs.…”

“…Pathogenic cell surface proteins are recognized by immune receptors and trigger downstream transcription factors such as Rel1 (Toll pathway), Rel2 (Imd pathway), and STAT (JAK-STAT pathway). Previous studies have evaluated how the expression of AMPs are induced by DENV infection in mosquitoes, and they exhibit antiviral activities ( 6 , 8 , 18 , 20 ). We further demonstrated that transgenic mosquitoes with TEP1 loss-of-function inhibited the expression of two AMPs and the transcription factor Rel2 of the Imd pathway.…”

“…The mechanisms involved in the regulation of AMPs via immune pathways have mainly been studied in Drosophila ( 6 , 8 , 19 ). In mosquitoes, Toll, Imd, and JAK-STAT pathways are activated during pathogen infection ( 6 , 8 , 19 , 20 ). Pathogenic surface proteins are recognized by immune receptors and trigger downstream transcription factors, such as Rel1 (Toll pathway), Rel2 (Imd pathway), and STAT (JAK-STAT pathway) ( 21 ).…”

“…Then, the activated transcription factors bind to specific regulatory elements for AMP gene transcription initiation ( 6 , 8 , 19 ). The JAK-STAT pathway has been shown to be activated by viral infection in mosquitoes ( 6 , 8 , 20 ). Previous studies also report that AMP expression may be induced by DENV infection in mosquitoes, and AMPs exhibit antiviral activity ( 6 , 8 , 18 , 20 ).…”