Global Cross-Talk of Genes of the Mosquito Aedes aegypti in Response to Dengue Virus Infection

Abstract

The mosquito Aedes aegypti is the primary vector of dengue virus (DENV) infection in humans, and DENV is the most important arbovirus across most of the subtropics and tropics worldwide. The early time periods after infection with DENV define critical cellular processes that determine ultimate success or failure of the virus to establish infection in the mosquito. To identify genes involved in these processes, we performed genome-wide transcriptome profiling between susceptible and refractory A. aegypti strains at two critical early periods after challenging them with DENV. Genes that responded coordinately to DENV infection in the susceptible strain were largely clustered in one specific expression module, whereas in the refractory strain they were distributed in four distinct modules. The susceptible response module in the global transcriptional network showed significant biased representation with genes related to energy metabolism and DNA replication, whereas the refractory response modules showed biased representation across different metabolism pathway genes including cytochrome P450 and DDT [1,1,1-Trichloro-2,2-bis(4-chlorophenyl) ethane] degradation genes, and genes associated with cell growth and death. A common core set of coordinately expressed genes was observed in both the susceptible and refractory mosquitoes and included genes related to the Wnt (Wnt: wingless [wg] and integration 1 [int1] pathway), MAPK (Mitogen-activated protein kinase), mTOR (mammalian target of rapamycin) and JAK-STAT (Janus Kinase - Signal Transducer and Activator of Transcription) pathways. Our data revealed extensive transcriptional networks of mosquito genes that are expressed in modular manners in response to DENV infection, and indicated that successfully defending against viral infection requires more elaborate gene networks than hosting the virus. These likely play important roles in the global-cross talk among the mosquito host factors during the critical early DENV infection periods that trigger the appropriate host action in susceptible vs. refractory mosquitoes. Dengue virus is primarily transmitted by Aedes aegypti mosquitoes. Control of the vector mosquito is the major practice to prevent dengue. However, it is not well known how the virus can infect some mosquito strains but fail to do so with other refractory strains. To address that question, we conducted whole genome microarray based gene expression studies between susceptible and refractory strains of A. aegypti to identify gene expression patterns following challenge with dengue virus. Our analysis of the early infection periods reveals that a large number of genes are involved in a highly coordinated manner either to host or defend against the virus. Genes responding to dengue infection were clustered in seven expression modules. Genes associated with susceptibility to infection were largely clustered in one expression module, while those associated with refractoriness were distributed in four distinct modules. A common core set of genes expressed in both susceptible and refractory individuals were clustered in two expression modules. We identified genes and specific pathways that potentially regulate compatible or non-compatible interactions between dengue virus and the mosquito, most notably energy metabolism and DNA replication in the susceptible response in contrast to cell growth and death in the refractory response.