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wMelpop strain of Wolbachia infection of Aedes albopictus mosquito C6/36 cells modulates dengue virus-induced host cellular transcripts and induces critical sequence alterations in dengue viral genome

ABSTRACT: The dengue virus (DENV) cause frequent epidemics infecting ~390 million people annually in over 100 countries. There are no approved vaccines or antiviral drugs for treatment of infected patients. However, there is a novel approach to control transmission of DENV by the mosquito vectors, Aedes aegypti and Ae. albopictus, using Wolbachia symbiont. The wMelPop strain of Wolbachia suppresses DENV transmission and shortens the mosquito life span. However, the underlying mechanism is poorly understood. To clarify this mechanism, either naïve Ae. albopictus (C6/36) or wMelPop-C6/36 cells were infected with DENV2. Analysis of host transcript profiles by RNAseq revealed that the presence of wMelPop had profound effects on mosquito host cell transcription in response to DENV2 infection. The viral RNA evolved from wMelPop-C6/36 contained low frequency mutations (~25%) within the coding region of transmembrane domain-1 (TMD1) of E protein. Mutations with >97 % frequencies were distributed within other regions of E, NS5 RNA-dependent RNA polymerase (NS5POL) domain, the TMDs of NS2A, NS2B, and NS4B. Moreover, while DENV2-infected naïve C6/36 cells showed syncytia formation, DENV2-infected wMelPop-C6/36 cells did not. The Wolbachia-induced mutant DENV2 can readily infect and replicate in naïve C6/36 cells; whereas, in the mutant DENV2- infected BHK-21 or Vero cells, the virus replication was delayed. In LLC-MK2 cells, the mutant failed to produce plaques. Additionally, in BHK-21 cells, many mutations in the viral genome reverted to WT and compensatory mutations in NS3 gene appeared. Our results suggest that wMelPop impacts significantly the interactions of DENV2 with mosquito and mammalian host cells.

ORGANISM(S): Aedes albopictus

PROVIDER: GSE125580 | GEO | 2019/02/25

REPOSITORIES: GEO

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Project description:Arboviruses are defined by their ability to replicate in both mosquito vectors and mammalian hosts. There is good evidence that arboviruses “prime” their progeny for infection of the next host, such as differential glycosylation of their outer glycoproteins or packaging of host ribosomal subunits. We and others have previously shown that mosquito derived viruses more efficiently infect mammalian cells than mammalian derived viruses. These observations are coherent with arboviruses acquiring host-specific adaptations, and we hypothesized that virus derived from either the mammalian host or mosquito vector will elicit different responses when infecting the mammalian host. Here we perform an RNA-sequencing analysis of the transcriptional response of Human Embryonic Kidney 293 (HEK-293) cells to infection with either mosquito (Aedes albopictus, C7/10) or mammalian (Baby Hamster Kidney, BHK) derived Sindbis virus (SINV). We show that C7/10 derived virus infection leads to a more robust transcriptional response in HEK-293s as compared to infection with the BHK derived virus. Surprisingly, despite more efficient infection, we found an increase in interferon-β (IFN-β) and interferon stimulated gene (ISG) transcripts in response to C7/10 derived virus infection versus BHK derived virus infection. However, translation of interferon stimulated genes was lower in HEK-293s infected with C7/10 derived virus, starkly contrasting with the transcriptional response. This inhibition of ISG translation is reflective of a more rapid overall shut-off of host cell translation following infection with C7/10 derived virus. Finally, we show that C7/10 derived virus infection of HEK-293 cells leads to elevated levels of phosphorylated eukaryotic translation elongation factor-2 (eEF2), identifying a potential mechanism leading to the more rapid shut-off of host translation. We postulate that the rapid shut-off of host translation in mammalian cells infected with mosquito derived virus acts to counter the IFN-β stimulated transcriptional response.

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wMelpop strain of Wolbachia infection of Aedes albopictus mosquito C6/36 cells modulates dengue virus-induced host cellular transcripts and induces critical sequence alterations in dengue viral genome

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