To be successfully transmitted to another susceptible human host by , dengue virus (DENV) must first successfully infect the mosquito midgut. The virus-host interactions that enable successful midgut infection, however, is not well understood. To understand the important interactions for successful midgut infection, we took advantage of the wild-type DENV2 16681 and its attenuated derivative PDK53, which has been shown to be refractory in mosquito infection. Using oral infectious-blood feeding, we observed that PDK53 failed to produce infectious progenies in the midgut, despite detectable viral genome replication. Furthermore, we found that the foci of PDK53 infection in the midgut, detected by immunofluorescence staining, was limited in both size and number, compared to its parent, 16681. Transcriptional analysis of the mosquito midgut revealed increased expression of genes in multiple innate immune pathways upon PDK53 infection but not 16681. To pinpoint the mutation responsible for this phenotype, we constructed an infectious clone of 16681 and used site-directed mutagenesis to substitute each of the known mutations in PDK53 into the 16681 genomic backbone. This approach pinpointed the NS1 G53D mutation as the single most important attenuating mutation in PDK53 in engendering refractoriness to mosquito midgut infection. Mechanistically, our data also suggests that this mutation affected the virus-ER-resident protein interactions that impacted the efficiency of DENV replication and hence induction of the innate immune response. Our findings reveal insights into the pathogenesis of dengue and adds to the body of knowledge on critical virushost interactions that govern epidemiological fitness of DENV.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.

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