Dengue virus (DENV) is the causative agent of dengue fever (DF) and the life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent mosquito-borne viral diseases worldwide. Signaling by type I interferon (IFN) is critical for protecting the host during DENV infection. Although the absence of one or multiple of transcription factors IRF-3, IRF-5, and IRF-7 in mice is sufficient to increase susceptibility to infection with various viruses, mice lacking all three (TKO) remain resistant to DENV challenge that is lethal in type I IFN receptor-deficient mice. This indicates the presence of an IRF-3, IRF-5, and IRF-7-independent (hereafter termed IRF-3/5/7-independent) mechanism against DENV that is required for host protection. Identification of this pathway is important because the transcriptional regulation of type IFN and interferon-stimulated gene (ISG) response for antiviral immunity is not fully understood, as new studies reveal that multiple transcription factors exist to regulate type I IFN production and ISG expression in a cell-specific host species-specific, time-specific, or virus-specific manner. In the proposed studies, we seek to define the transcription factors that are responsible for protection against DENV despite the absence of major transcription factors IRF-3, IRF-5, and IRF-7 in both mouse and human macrophages. Our preliminary data suggest that the IRF-3/5/7-independent pathway is type I IFN-dependent. We will test the hypothesis that in the absence of IRF-3, IRF-5, and IRF-7, type I IFN and ISG responses still occur to protect against DENV, potentially through activities of IRF-1, ELF4, or other transcription factors with previously unknown relation to antiviral immunity.
The Specific Aims are: 1. To investigate the role of type I IFN signaling in the IRF-3/5/7-independent mechanism of protection against DENV infection. 2. To evaluate the role of IRF-1 and ELF4 in the IRF-3/5/7-independent pathway. 3. To identify novel transcription factors that regulate the IRF-3/5/7-independent pathway.
Understanding the transcriptional regulation of pathways that provide protection against DENV is important for identifying the most relevant and effective targets that influence type I IFN production and ISG induction. Knowledge gained from this project will be broadly applicable to a range of viruses in addition to DENV. Safe and effective therapeutics against DENV and other flaviviruses are urgently needed, because global endemic regions are expanding, and there is broader circulation of different flaviviruses and DENV serotypes within the US.
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