Anti-Bacterial Innate Responses Enhance Paramyxovirus Replication

抗菌先天反应增强副粘病毒复制

• 批准号: 7656952
• 负责人: Griffith D. Parks
• 金额: $ 18.5万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656952
• 关键词: Agonist; Anti-Bacterial Agents; Antiviral Agents; Apoptosis; Bacteria; Bacterial Infections; Caregivers; Cell Proliferation; Cell Survival; Cells; Child; Chronic Bronchitis; Data; Dendritic Cells; Environment; Epithelial Cells; Eukaryotic Cell; Gene Expression; Goals; Growth; Hearing; Human; Human Metapneumovirus; Human respiratory syncytial virus; Immune; Immune response; Impairment; In Vitro; Infection; Lead; Measures; Mediating; Microbe; Microbial Biofilms; Modeling; Nontypable Haemophilus influenza; Otitis Media; Paramyxovirus; Parents; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Quality of life; RNA Viruses; Receptor Signaling; Recurrence; Rhinovirus; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Simian virus 5; Sinusitis; Speech; Streptococcus pneumoniae; TLR2 gene; Testing; Tissues; Toll-Like Receptor 2; Toll-Like Receptor Pathway; Toll-like receptors; Up-Regulation; Viral; Virus; Virus Replication; Work; antimicrobial; base; clinically relevant; influenzavirus; inhibitor/antagonist; innovation; interest; microbial; monocyte; mutant; novel therapeutics; parainfluenza virus; public health relevance; response

DESCRIPTION (provided by applicant): The human upper airway and associated tissues harbor a diverse microbial flora. There is increasing evidence that polymicrobial infections involving bacteria and paramyxoviruses are a significant factor in human patients with chronic bronchitis, sinusitis and otitis media. Sequelae of recurrent otitis media include hearing and speech impairment that significantly impact the quality of life of both children and their parents/caregivers. Thus, there is a gap in our understanding of interactions between viral and bacterial infections as well as the impact of these microbes on immune responses. Traditionally, TLR signaling pathways have been categorized as anti-microbial, since in most cases their activation leads to innate immune responses and to restricted bacterial or viral growth. This application is based on our remarkable finding that exposure of primary human monocyte-derived cells to bacterial Toll- like receptor (TLR) agonists leads to: 1) enhanced paramyxovirus gene expression and 2) a reversal of virus-induced apoptosis. We propose that activation of TLR pathways by bacterial components does not always lead to strictly anti-microbial responses, but rather, can actually create cell environments that enhance virus replication. The central hypotheses to be tested here are that bacterially-derived TLR agonists enhance RNA virus replication through i) activation of cell survival/proliferation pathways, or ii) suppression of antiviral pathways. In Aim 1, we will test these two mechanistic hypotheses by which bacterial components enhance paramyxovirus gene expression and rescue virus-induced apoptosis. In Aim 2, we will extend these studies to determine if our preliminary results apply to other clinically-relevant RNA viruses such as respiratory syncytial virus, human parainfluenza virus, human metapneumovirus, influenza virus, and rhinovirus. In Aim 3, we will establish in vitro bacterial biofilms with nontypeable Haemophilus influenzae (NTHi) or with Streptococcus pneumoniae (pneumococcus) and determine the viral replication potential in immune and epithelial cells exposed to bacterial biofilms or biofilm-derived components. Our studies are innovative, as they show that "anti-microbial" signaling can actually create environments that promote virus replication, particularly for viral mutants which would otherwise be restricted. At the completion of this project, we will have established a firm baseline to study interactions between bacteria, viruses and the host cell signaling pathways that can modulate their replication potential. PUBLIC HEALTH RELEVANCE: There is increasing evidence that polymicrobial infections involving bacteria and paramyxoviruses are a significant factor in human patients with chronic bronchitis, sinusitis and otitis media, and the sequelae of recurrent otitis media can include hearing and speech impairment. We will test the hypotheses that bacterially-derived TLR agonists enhance RNA virus replication through i) activation of cell survival/proliferation pathways, or ii) suppression of antiviral pathways. Our studies are innovative, as they show that "anti-microbial" signaling can actually create environments that promote virus replication, particularly for viral mutants which would otherwise be restricted.

描述（由申请人提供）：人类上呼吸道和相关组织含有多种微生物菌群。越来越多的证据表明，涉及细菌和副粘病毒的多种微生物感染是人类慢性支气管炎、鼻窦炎和中耳炎患者的一个重要因素。复发性中耳炎的后遗症包括听力和言语障碍，严重影响儿童及其父母/照顾者的生活质量。因此，我们对病毒和细菌感染之间的相互作用以及这些微生物对免疫反应的影响的理解存在差距。传统上，TLR 信号通路被归类为抗微生物信号通路，因为在大多数情况下，它们的激活会导致先天免疫反应并限制细菌或病毒的生长。该应用基于我们的显着发现，即原代人单核细胞衍生的细胞暴露于细菌 Toll 样受体 (TLR) 激动剂会导致：1) 副粘病毒基因表达增强，2) 病毒诱导的细胞凋亡逆转。我们认为，细菌成分激活 TLR 通路并不总是会导致严格的抗微生物反应，而是实际上可以创造增强病毒复制的细胞环境。这里要测试的中心假设是细菌来源的 TLR 激动剂通过 i) 激活细胞存活/增殖途径，或 ii) 抑制抗病毒途径来增强 RNA 病毒复制。在目标 1 中，我们将测试这两种机制假设，通过这些假设，细菌成分可以增强副粘病毒基因表达并挽救病毒诱导的细胞凋亡。在目标 2 中，我们将扩展这些研究，以确定我们的初步结果是否适用于其他临床相关的 RNA 病毒，例如呼吸道合胞病毒、人类副流感病毒、人类偏肺病毒、流感病毒和鼻病毒。在目标 3 中，我们将用不可分型的流感嗜血杆菌 (NTHi) 或肺炎链球菌（肺炎球菌）建立体外细菌生物膜，并确定暴露于细菌生物膜或生物膜衍生成分的免疫和上皮细胞中的病毒复制潜力。我们的研究具有创新性，因为它们表明“抗微生物”信号实际上可以创造促进病毒复制的环境，特别是对于原本会受到限制的病毒突变体。该项目完成后，我们将建立一个坚实的基线来研究细菌、病毒和宿主细胞信号通路之间的相互作用，从而调节它们的复制潜力。公共卫生相关性：越来越多的证据表明，涉及细菌和副粘病毒的多种微生物感染是人类慢性支气管炎、鼻窦炎和中耳炎患者的一个重要因素，而复发性中耳炎的后遗症可能包括听力和言语障碍。我们将测试以下假设：细菌来源的 TLR 激动剂通过 i) 激活细胞存活/增殖途径，或 ii) 抑制抗病毒途径来增强 RNA 病毒复制。我们的研究具有创新性，因为它们表明“抗微生物”信号实际上可以创造促进病毒复制的环境，特别是对于否则会受到限制的病毒突变体。