De Novo DNA Synthesis in Aedes aegypti Midgut Cells as a Complementary Strategy to Limit Dengue Viral Replication

Abstract

Aedes aegypti is the main vector of Dengue Virus, carrying the virus during the whole mosquito life post-infection. Few mosquito fitness costs have been associated to the virus infection, thereby allowing for a swift dissemination. In order to diminish the mosquito population, public health agency use persistent chemicals with environmental impact for disease control. Most countries barely use biological controls, if at all. With the purpose of developing novel Dengue control strategies, a detailed understanding of the unexplored virus-vector interactions is urgently needed. Damage induced (through tissue injury or bacterial invasion) DNA duplication (endoreplication) has been described in insects during epithelial cells renewal. Here, we delved into the mosquito midgut tissue ability to synthesize DNA de novo; postulating that Dengue virus infection could trigger a protective endoreplication mechanism in some mosquito cells. We hypothesized that the Aedes aegypti orthologue of the Drosophila melanogaster hindsight gene (not previously annotated in Aedes aegypti transcriptome/genome) is part of the Delta-Notch pathway. The activation of this transcriptional cascade leads to genomic DNA endoreplication. The amplification of the genomic copies of specific genes ultimately limits the viral spreading during infection. Conversely, inhibiting DNA synthesis capacity, hence endoreplication, leads to a higher viral replication.

Immune priming with inactive dengue virus during the larval stage of Aedes aegypti protects against the infection in adult mosquitoes

“…The mechanisms behind immune priming induced from the larval stage have not been ascertained yet. Nevertheless, we have recently observed that DNA synthesis and endoreplication participates in the immune priming of adult mosquitoes against DENV and Plasmodium 6,7 . Immune priming in the Anopheles albimanus LSB-AA695BB cell line induced DNA synthesis, increasing the number of TEP and PPO1 gene-copies 7 .…”

DNA Synthesis Is Activated in Mosquitoes and Human Monocytes During the Induction of Innate Immune Memory

“…albimanus and Aedes aegypti mosquitoes. This indicates that DNA synthesis and endoreplication are part of the mechanisms of memory ( 24 , 25 ). Cisplatin treatment causes the same outcome in monocytes and mosquito cell lines, reducing the expression of the immune response genes related to innate immune memory.…”

“…The same occurs in the case of Aedes aegypti infected with dengue virus. When DNA synthesis is blocked by cisplatin, dengue virus is able to replicate in the mosquito midgut ( 24 , 25 ). Hence, midgut cells apparently require the amplification of certain genes, such as TEP1 or PPO1 (but not CTL s), for a fast and effective immune response.…”

“…In another study by our group, enhanced DNA synthesis was observed in the midgut of An. albimanus mosquitoes after the second exposure to the same pathogen ( 23 ), and more recently in Aedes aegypti mosquitoes treated with the dengue virus ( 24 , 25 ). In the latter effort, we also explored the role played by one of the key elements, hindsight ( HNT , a zinc-finger transcription factor), in cell cycle switching toward endoreplication.…”

Investigating the role of microRNAs in Wolbachia-Aedes aegypti-dengue virus interactions

“…This recently reported phenomenon (Serrato-Salas et al, 2018b), involves increases in de novo DNA synthesis in the midguts of Aedes mosquitoes challenged with inactive DENV-2 particles as well as increased activation of the hindsight and Delta-Notch orthologues. These pathways confer a defence against biotic challenges to mosquitoes by allowing them to rapidly renew tissue in the midgut and thus limit pathogen proliferation (Serrato-Salas et al, 2018a). Insects previously exposed to inactive virus particles seemingly mounted a higher anti-viral response and subsequently the level of DENV infection was greatly reduced compared to naive mosquitoes.…”