| Summary: | 碩士 === 國立成功大學 === 微生物及免疫學研究所 === 103 === Dengue virus (DENV) infection causes a wide range of disease ranging from dengue fever to potentially fatal dengue hemorrhagic fever or dengue shock syndrome. Currently there are no approved vaccines or antiviral drugs against dengue infection. Innate immune responses, particularly type-I interferon (IFN-α/β), are the first lines of defense against viral infections. Unfortunately, DENV interacts with host factors to escape from IFN responses, and the detailed mechanisms are not totally understood. Integrin-linked kinase (ILK) is a widely expressed serine/threonine protein kinase which connects extracellular molecules to intracellular signaling pathways. By activating ILK, a number of cellular functions can be modulated, including tumorigenesis or Coxsackievirus B3 replication. However, the role of ILK in DENV infection remains uncertain. Here, we showed that dengue viral titers are reduced in ILK inhibited cells. Moreover, inhibition of ILK suppresses DENV replicon expression, but no difference is seen in DENV binding in both control and ILK-silenced cells. This indicates that ILK is required for DENV replication after virus entry. Hence, we further investigated whether ILK regulates DENV replication through the IFN pathway. Our results revealed that there is no difference in induction of IFNα/β between DENV-infected control and ILK-silenced cells. Nevertheless, the downstream responses of IFNs, such as STAT1/2 activation or interferon-stimulated genes (ISG) expression, were upregulated in DENV-infected ILK-silenced cells. In contrast, the suppressor of cytokine signaling 3 (SOCS3), which is able to block IFNs signaling is suppressed. This ILK-mediated SOCS3 induction was found to antagonize DENV infection-triggered IFN signaling and ISG expression. Furthermore, we clarified that ILK may activate the Akt/ERK/NF-κB pathway to induce SOCS3 expression that is required for DENV replication. In conclusion, we uncovered a new regulatory role of ILK in IFN signaling, and targeting ILK may be a potential antiviral therapeutic for future drug development.
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