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The establishment of a productive dengue virus (DENV) infection in the midgut epithelial cells of Aedes aegypti is critical for the viral transmission cycle. The hypothesis that DENV virions interact directly with specific mosquito midgut proteins was explored. We found that DENV serotype 2 (DENV2) pretreated with trypsin interacted with a single 31 kDa protein, identified as AAEL011180 by protein mass spectrometry. This putative receptor is a highly conserved protein and has orthologs in culicine and anopheline mosquitoes. We confirmed that impairing the expression of AAEL011180 in the midgut of Ae. aegypti females abolished the interaction with DENV2, and the virus also bound to immobilized recombinant purified receptor. Furthermore, recombinant DENV2 surface E glycoprotein bound to recombinant AAEL011180 with high affinity (38.2 nM) in binding kinetic analysis using surface plasmon resonance. The gene for this DENV2 E protein receptor (EPrRec) was disrupted, but since the gene is essential in Ae. aegypti, only heterozygote knockout (ΔEPrRec+/−) females could be recovered. Further reducing EPrRec mRNA expression in the midgut of ΔEPrRec+/− females by systemic dsRNA injection significantly reduced the prevalence of DENV2 midgut infection. EPrRec also interacts with heat shock protein 70 cognate 3 (Hsc70-3), and silencing Hsc70-3 expression in ΔEPrRec females also reduced the prevalence of DENV2 midgut infection. [ABSTRACT FROM AUTHOR]

Importance: Malaria transmission by Anopheles gambiae mosquitoes is very effective, in part because the parasite expresses a surface protein called Pfs47 that allows it to evade the mosquito immune system. Here we investigate how this protein changes the response of mosquito midgut epithelial cells to invasion by the parasite. Pfs47 is known to interact with P47Rec, a mosquito midgut receptor. We found that Pf47Rec inhibits caspase-mediated apoptosis by interacting with the Hsc70-3. This disrupts nitration of midgut epithelial cells invaded by the parasite and the release of hemocyte-derived microvesicles, which are critical for effective activation of the mosquito complement system that eliminates the parasite., Competing Interests: The authors declare no conflict of interest.