In this review, we discuss how the host cell activates innate immunity in response to DENV infection and the strategies DENV uses to evade the innate immune system.
We illustrate the main theme of this article in Figure 1 and summarize the DENV antagonism Table 1 described in the text. Figure 1. Refer to the main text for details. Table 1. DENV belongs to the genus Flavivirus of Flaviviridae and is the leading cause of mosquito-borne viral diseases. The DENV invasion starts with cell-surface attachment and receptor binding. After internalization, the nucleocapsid is uncoated, and the virus genome then releases to the cytoplasm.
Ultimately, the mature and infectious virions are secreted into the extracellular space and await the next round of infection 19 , DENV has evolved many strategies to minimize its exposure in vitro because the virus is membrane-enveloped and is liable to dysfunction in vitro. Thus, DENV uses the mosquito, the natural syringe, as the vector to preserve, replicate, and transmit itself. Despite the presence of a protein D7 capable of inhibiting DENV in mosquito saliva 23 , the bites with mosquito saliva increase DENV dissemination into the mammalian host 24 , DENV takes advantage of the mammalian host machinery for replication, but the immune system can detect and attack this invading pathogen.
Once activated, the sensor hands over the signal to its adaptor proteins, which then recruit kinases to phosphorylate transcription factors and ultimately turn on the production of antiviral IFNs and proinflammatory cytokines.
Various antiviral proteins interfere with steps of the viral lifecycle. We categorized these various strategies by the stages of IFN system and discussed them below.
Camouflage is the first strategy to keep DENV away from the alarm bell of innate immunity. Therefore, DENV hides and stays under the radar in host cells. DENV enters host cells by receptor-mediated endocytosis, and its RNA is released to the cytosol for translation and replication. Both contain two caspase activation and recruitment domains CARDs at the N-terminus for antiviral signaling initiation. The cellular DNA should be located in the nucleus or mitochondria.
Presence of a DNA molecule in the cytoplasm is thus expected to trigger innate immune responses, such as inflammation and IFN production The roles of mitochondria in innate immunity were largely unknown until strong antiviral activity was detected by overexpressing the mitochondrial protein MAVS 47 — Mitochondria move along the cytoskeleton and continuously undergo fusion and fission, which results in the diverse morphology of each mitochondrion 82 , MAVS forms prion-like aggregates upon activation 84 , which also leads mitochondria to become aggregated in cells overexpressing MAVS Therefore, manipulation of mitochondrial dynamics may regulate antiviral activity in response to virus infection.
Indeed, overexpression of the mitochondrial fusion mediator mitofusin 1 MFN1 rather than MFN2 resulted in a higher-order aggregation of mitochondria that facilitated IFN-induction signaling In contrast, MAVS-mediated IFN-induction signaling was dampened in cells harboring highly fragmented mitochondrial morphology, either by overexpressing a dominant-negative MFN1 12 , 85 or by administration of a chemical disrupting mitochondrial membrane potential MMP To manipulate mitochondria toward fragmentation, the virus may suppress fusion or enhance fission.
Hence, mitochondria may serve as platforms transmitting the IFN-induction signal, so that aggregated mitochondria help form a more operative signosome by tethering related molecules with each other. This notion is also consistent with the scenario that disrupted mitochondrial fusion or misassembled signosome leads to disturbed IFN-induction signaling in DENV-infected cells. With DENV infection, disease symptoms range from asymptomatic, classical dengue fever to life-threatening dengue hemorrhagic fever and severe dengue shock syndrome.
The diverse disease symptoms result from a complicated interaction between DENV and the host. Innate immunity helps the host fight against infection by eliminating DENV and regulating follow-up immune responses. DENV may defeat the host immunity at first line of defense. The seesaw of DENV-inducing and -antagonizing innate immunity in the initial state of infection may contribute to the DENV pathogenesis at some later time. Recent evidence shows that both viral and cellular factors are involved in the host responses upon DENV infection.
Therefore, we highlight critical regulatory mechanisms of innate immunity by showing how DENV manipulates it. Notwithstanding unfinished puzzles, antiviral applications derived from all these studies are anticipated. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Innate immunity evasion by dengue virus. Viruses — Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol. Innate immune escape by dengue and West Nile viruses. Curr Opin Virol. Cell Host Microbe —4. Science — Inhibition of interferon signaling by dengue virus. Nat Microbiol. PLoS Pathog. Dengue virus targets the adaptor protein MITA to subvert host innate immunity. Showing Slide 1 of 1. Picture Information. Mouse over to Zoom - Click to enlarge.
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