Virus-Host Interactions: Induction and Evasion of Host Innate Immunity

病毒与宿主的相互作用：宿主先天免疫的诱导和逃避

• 批准号: 9354888
• 负责人: Sonja Best
• 金额: $ 185.24万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354888
• 关键词: Affect; Amino Acids; Animal Model; Antigen Presentation; Antiviral Response; Arthropods; Automobile Driving; B-Cell Activation; Binding; Biology; Capsid; Categories; Cell Survival; Cell physiology; Cells; Central Nervous System Infections; Characteristics; Cleaved cell; Clinical; Collaborations; Complex; Culicidae; Dendritic Cells; Dengue Virus; Development; Disease; Endoplasmic Reticulum; Filovirus; Flavivirus; Flavivirus Infections; Gene Expression; Genes; Genome; Goals; Host resistance; Hour; Human; Immune; Immune response; Immune system; Infection; Inflammation Mediators; Interferon Type I; Interferons; Intervention; Janus kinase; Japanese encephalitis virus; Laboratories; Langat virus; Lead; Ligation; Membrane; Methyltransferase; Modeling; Mus; NF-kappa B; National Institute of Allergy and Infectious Disease; Natural Immunity; Nonstructural Protein; Nucleic Acids; Open Reading Frames; Pathogenesis; Pathway interactions; Pattern recognition receptor; Peptide Hydrolases; Polyproteins; Proteins; RNA; RNA Helicase; RNA Processing; RNA Viruses; RNA-Directed RNA Polymerase; Recovery; Research; Role; STAT2 gene; Signal Transduction; Signal Transduction Pathway; Site; TNF gene; TRIM Gene; Therapeutic; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Ticks; Toll-like receptors; Transcriptional Activation; Transducers; Translating; Tretinoin; Vaccines; Viral; Viral Hemorrhagic Fevers; Viral Nonstructural Proteins; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; Yellow fever virus; Zika Virus; adaptive immunity; base; burden of illness; cell type; chemokine; cytokine; immune activation; improved; macrophage; member; mouse model; new therapeutic target; nonhuman primate; novel; pathogen; programs; response; success; therapeutic target; transcription factor; ubiquitin-protein ligase; vector; virus host interaction; virus pathogenesis

The host innate immune response is triggered within hours of virus infection. As a whole, its function is to limit virus replication at local sites of infection and to orchestrate development of the adaptive immune response. Viruses are typically recognized by cellular pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and the retinoic acid inducible gene (RIG)-like RNA helicases (RLHs). Ligation of these PRRs, often by viral nucleic acids, culminates in the activation of multiple transcription factors that cooperate in driving expression of cytokines and chemokines characteristic of the innate response. Nuclear factor-kappa B (NF-kappaB) and interferon (IFN) regulatory factors (IRFs) are particularly important transcription factors, responsible for induction of type I IFN (IFNalpha/beta), tumor necrosis factor alpha (TNFalpha) and other mediators of inflammation. IFNalpha/beta is central to the anti-viral response as it initiates its own transcriptional program resulting in expression of IFN-stimulated genes (ISGs) via the Janus kinase-signal transducer and activation of transcription (JAK-STAT) pathway. ISG expression influences many cellular processes including RNA processing, protein stability and cell viability that can directly affect virus replication. ISG expression in cells of the immune system such as dendritic cells (DCs) and macrophages is critical for antigen presentation and T- and B-cell activation, thus affecting the quality of the adaptive immune response and eventual virus clearance. To facilitate dissemination, pathogenic viruses have evolved mechanisms to suppress host innate immunity by antagonizing these signal transduction pathways. Hence, understanding the specific pathways by which viruses activate and evade innate immune responses is essential for understanding viral pathogenesis as well as for development of effective vaccines. To examine virus-host interactions that affect innate immunity, our laboratory utilizes flaviviruses as the primary model of infection. Flaviviruses have an essentially global distribution and represent a tremendous disease burden to humans, causing millions of infections annually. The success of flaviviruses as human pathogens is associated with the fact that they are arthropod-borne, transmitted by mosquitoes or ticks. Significant members of this group include dengue virus (DENV) and yellow fever virus (YFV) that cause hemorrhagic fevers, as well as Japanese encephalitis virus (JEV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV) and most recently Zika virus (ZIKV) that cause infections of the central nervous system. These viruses are listed as NIAID category A, B and C pathogens for research into their basic biology and host response. The flavivirus single-stranded RNA genome is translated as one open reading frame; the resulting polyprotein is cleaved into at least ten proteins that include three structural (capsid C, membrane M, derived from the precursor preM and envelope E), and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). Virus replication proceeds in association with modified membranes derived from the endoplasmic reticulum of host cells. NS5 is the largest and most conserved of the flavivirus proteins containing approximately 900 amino acids. It encodes a methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRP) and associates with NS3 (the viral protease) to form the functional unit of the viral replication complex. Despite the widespread and often severe infections caused by these pathogens, vaccines exist for only a few (YFV, JEV and TBEV) and no therapeutic exists to treat clinical infection caused by any flavivirus. Type I IFNs are essential to recovery from flavivirus infection and have been used clinically as potential therapeutics, albeit with limit success. This may be due to the observation that all flaviviruses examined to date antagonize IFN-dependent responses by suppressing JAK-STAT signal transduction. We identified NS5 as the major IFN antagonist encoded by flaviviruses, originally using Langat virus (LGTV; a member of the TBEV complex of flaviviruses) and more recently using WNV. Although other NS proteins contribute to suppression of JAK-STAT signaling, studies by our laboratory and others suggest that NS5 is the most potent of the IFN antagonist proteins encoded by all vector-borne flaviviruses examined thus far. Hence, determining the mechanism(s) by which NS5 impedes signaling is essential to understand flavivirus pathogenesis and may lead to new therapeutic targets. Furthermore, it is important to understand the mechanisms underlying the anti-viral effects of IFN by identifying the function of ISGs with anti-viral activity. Finally, it is essential to translate these findings to immunologically relevant cell types and animal models to understand the roles of induction and evasion of innate immunity in development of the adaptive immune response and in virus pathogenesis. Achieving these goals will significantly improve our understanding of how viruses emerge and cause disease in humans, as well as identify therapeutic targets for intervention. The major advance in our work this year was a collaboration with Dr. Adolfo Garcia-Sastre's laboratory resulting in the identification of NS5 from Zika virus as an antagonist of type I IFN signaling. NS5 from Zika virus binds and degrades STAT2 from humans and non-human primates, but not mice, which may explain why mouse models of Zika virus infection have to be deficient in IFN signaling in order to observe disease. We also noted that the strategy of Zika virus NS5 to degrade STAT2 is similar to that of dengue virus but not its closer relative called Spondweni virus.However, unlike dengue virus, Zika virus did not utilize the E3 ubiquitin ligase UBR4 to induce degradation suggesting that there is another mechanism that is yet to be identified.

宿主的先天免疫反应在病毒感染数小时内被触发。总的来说，它的功能是限制病毒在局部感染部位的复制，并协调适应性免疫反应的发展。病毒通常由细胞模式识别受体（PRRs）识别，包括toll样受体（TLRs）和视黄酸诱导基因（RIG）样RNA解旋酶（RLHs）。通常通过病毒核酸连接这些PRRs，最终激活多个转录因子，这些转录因子协同驱动先天反应特征的细胞因子和趋化因子的表达。核因子- κ B （nf - κ B）和干扰素（IFN）调节因子（irf）是特别重要的转录因子，负责诱导I型IFN （IFN - α / β）、肿瘤坏死因子α (TNFalpha)和其他炎症介质。ifn - α / β是抗病毒反应的核心，因为它启动自己的转录程序，通过Janus激酶信号传感器和转录激活（JAK-STAT）途径导致ifn刺激基因（ISGs）的表达。ISG的表达影响许多细胞过程，包括RNA加工、蛋白质稳定性和细胞活力，这些过程可以直接影响病毒复制。免疫系统细胞如树突状细胞（dc）和巨噬细胞中的ISG表达对于抗原呈递和T细胞和b细胞活化至关重要，从而影响适应性免疫反应的质量和最终的病毒清除。为了促进传播，致病性病毒已经进化出通过拮抗这些信号转导途径来抑制宿主先天免疫的机制。因此，了解病毒激活和逃避先天免疫反应的特定途径对于了解病毒的发病机制以及开发有效的疫苗至关重要。