Abstract
The actions of the RIG-I like receptor (RLR) and type I interferon (IFN) signaling pathways are essential for a protective innate immune response against the emerging flavivirus West Nile virus (WNV). In mice lacking RLR or IFN signaling pathways, WNV exhibits enhanced tissue tropism, indicating that specific host factors of innate immune defense restrict WNV infection and dissemination in peripheral tissues. However, the immune mechanisms by which the RLR and IFN pathways coordinate and function to impart restriction of WNV infection are not well defined. Using a systems biology approach, we defined the host innate immune response signature and actions that restrict WNV tissue tropism. Transcriptional profiling and pathway modeling to compare WNV-infected permissive (spleen) and nonpermissive (liver) tissues showed high enrichment for inflammatory responses, including pattern recognition receptors and IFN signaling pathways, that define restriction of WNV replication in the liver. Assessment of infected livers from Mavs−/−×Ifnar−/− mice revealed the loss of expression of several key components within the natural killer (NK) cell signaling pathway, including genes associated with NK cell activation, inflammatory cytokine production, and NK cell receptor signaling. In vivo analysis of hepatic immune cell infiltrates from WT mice demonstrated that WNV infection leads to an increase in NK cell numbers with enhanced proliferation, maturation, and effector action. In contrast, livers from Mavs−/−×Ifnar−/− infected mice displayed reduced immune cell infiltration, including a significant reduction in NK cell numbers. Analysis of cocultures of dendritic and NK cells revealed both cell-intrinsic and -extrinsic roles for the RLR and IFN signaling pathways to regulate NK cell effector activity. Taken together, these observations reveal a complex innate immune signaling network, regulated by the RLR and IFN signaling pathways, that drives tissue-specific antiviral effector gene expression and innate immune cellular processes that control tissue tropism to WNV infection.
Highlights
Acute virus infection induces host innate immune defense programs that serve to control virus replication, prevent virusmediated pathology, and aid in developing sterilizing immunity
Upon binding virusspecific RNA structures and target nucleic acid sequences, RIG-I and MDA5 undergo conformational change and interact with the adaptor protein MAVS, leading to activation of NF-kB and interferon regulatory factor (IRF), including IRF-3 and IRF-7, that drive transcription of antiviral target genes, interferon-b, proinflammatory cytokines, and hundreds of interferon-stimulated genes (ISGs) [1,3]. This host response is further amplified by signaling through the type I interferon (IFN) receptor that drives the formation of the multimeric interferon-stimulated gene factor 3 (ISGF3), consisting of IRF-9, STAT2 and/or STAT1, that binds to interferon-stimulated response promoter elements (ISRE) and further amplifies the transcription of ISGs
We demonstrate that the RIG-I like receptors (RLR) and type I IFN signaling axis plays an essential role in protection against West Nile virus (WNV) infection and functions in a tissue-specific manner to control virus replication and restrict tissue tropism
Summary
Acute virus infection induces host innate immune defense programs that serve to control virus replication, prevent virusmediated pathology, and aid in developing sterilizing immunity (i.e. humoral and cell-mediated immunity). Upon binding virusspecific RNA structures and target nucleic acid sequences, RIG-I and MDA5 undergo conformational change and interact with the adaptor protein MAVS, leading to activation of NF-kB and interferon regulatory factor (IRF), including IRF-3 and IRF-7, that drive transcription of antiviral target genes, interferon-b, proinflammatory cytokines, and hundreds of interferon-stimulated genes (ISGs) [1,3] This host response is further amplified by signaling through the type I interferon (IFN) receptor that drives the formation of the multimeric interferon-stimulated gene factor 3 (ISGF3), consisting of IRF-9, STAT2 and/or STAT1, that binds to interferon-stimulated response promoter elements (ISRE) and further amplifies the transcription of ISGs. While several studies have identified key innate immune host factors in controlling virus replication and protection, little is known about context (specific cell types and organs) and how these processes regulate innate immune responses to restrict tropism of virus infection. After subcutaneous footpad inoculation in mice, WNV initially replicates in the skin at the inoculation site and the draining popliteal lymph node, resulting in Author Summary
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