The Ras/ERK signaling pathway couples antimicrobial peptides to mediate resistance to dengue virus in Aedes mosquitoes

Abstract

Aedes mosquitoes can transmit dengue and several other severe vector-borne viral diseases, thereby influencing millions of people worldwide. Insects primarily control and clear the viral infections via their innate immune systems. Mitogen-Activated Protein Kinases (MAPKs) and antimicrobial peptides (AMPs) are both evolutionarily conserved components of the innate immune systems. In this study, we investigated the role of MAPKs in Aedes mosquitoes following DENV infection by using genetic and pharmacological approaches. We demonstrated that knockdown of ERK, but not of JNK or p38, significantly enhances the viral replication in Aedes mosquito cells. The Ras/ERK signaling is activated in both the cells and midguts of Aedes mosquitoes following DENV infection, and thus plays a role in restricting the viral infection, as both genetic and pharmacological activation of the Ras/ERK pathway significantly decreases the viral titers. In contrast, inhibition of the Ras/ERK pathway enhances DENV infection. In addition, we identified a signaling crosstalk between the Ras/ERK pathway and DENV-induced AMPs in which defensin C participates in restricting DENV infection in Aedes mosquitoes. Our results reveal that the Ras/ERK signaling pathway couples AMPs to mediate the resistance of Aedes mosquitoes to DENV infection, which provides a new insight into understanding the crosstalk between MAPKs and AMPs in the innate immunity of mosquito vectors during the viral infection.

Functional conservation in genes and pathways linking ageing and immunity

“…Nevertheless, the regulation of immunity conferred by this pathway could depend on the pathogen. Additional reports indicate that ERK MAPK activation restricts replication of viruses after oral infection in D. melanogaster, and this function could be conserved in Aedes mosquitos [127,128].…”

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.…”

Midgut Epithelial Dynamics Are Central to Mosquitoes’ Physiology and Fitness, and to the Transmission of Vector-Borne Disease

“…In the mosquito midgut epithelium, there is some evidence that blood-feeding stimulates compositional changes. In the Aedes albopictus midgut, blood-feeding induces phosphorylation of ERK, a kinase in the EGFR pathway ( Liu et al, 2020 ) which, in Drosophila ISCs, is sufficient to drive proliferation ( Buchon et al, 2010 ). We propose that the pro-proliferative response to JH and 20E may be conserved in the midguts of mosquito species, helping to prepare the epithelium for the task of digesting blood.…”