Abstract
BackgroundThe 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.Methods and ResultsTo 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.ConclusionsOur 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.
Highlights
Dengue virus (DENV) represents a significant challenge for global public health where 2.5 billion people are estimated to be at risk of dengue related diseases [1,2,3]
Our data revealed extensive transcriptional networks of mosquito genes that are expressed in modular manners in response to dengue virus (DENV) infection, and indicated that successfully defending against viral infection requires more elaborate gene networks than hosting the virus
The A. aegypti genes responsive to the critical early stages of DENV infection were identified by a genome-wide transcriptome assay carried out using a NimbleGen oligonucleotide microarray format in MOYO-S (MS, susceptible to DENV) and MOYO-R (MR, refractory to DENV) females, upon challenging them with the JAM1409 strain of DENV
Summary
Dengue virus (DENV) represents a significant challenge for global public health where 2.5 billion people are estimated to be at risk of dengue related diseases [1,2,3]. The mosquito Aedes aegypti is the primary global vector of DENV. Upon mosquito blood feeding on a viremic human, DENV enters the mosquito mid-gut with the blood meal where it must establish an infection in mid-gut epithelial cells, the success of which is required for subsequent completion of the viral life cycle in the mosquito. Several anatomical barriers including mid-gut infection barriers (MIB) or mid-gut escape barriers (MEB) contribute to reduced susceptibility of A. aegypti mosquitoes to DENV [5]. Though these infection barriers have been demonstrated to be influenced by genes within multiple quantitative trait loci (QTL), the specific genes involved in conferring these infection barriers have not been identified. 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
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