The incidence and geographic range of dengue and dengue hemorrhagic fever has increased dramatically in recent decades. With 2.5 billion people now living in areas at risk for epidemic transmission, dengue has become the most important mosquito-borne viral disease affecting humans. Dengue virus (DENV) is a positive-strand RNA virus of the family Flaviviridae. It exists as four closely related but antigenically distinct serotypes, all of which have Aedes aegypti mosquitoes as their primary vector, with A. albopictus as a secondary vector.
Mosquitoes, like all insects, are exposed to a variety of microbes in their natural habitats, and possess an innate immune system that is capable of mounting a potent response against microbial challenge. The insect innate immune response is largely regulated by three main immune signaling pathways: the Toll, immune deficiency (IMD) and Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways. The Toll pathway is involved in defense against fungi, Gram-positive bacteria, and viruses, and has been found to be specifically involved in the A. aegypti anti-DENV response.
In order to study the interaction of DENV with the A. aegypti immune response, researchers have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a Gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with Gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with Gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology.