Influenza A Virus Infection Damages Zebrafish Skeletal Muscle and Exacerbates Disease in Zebrafish Modeling Duchenne Muscular Dystrophy.

Michelle Goody, Denise Jurczyszak, Carol Kim, Clarissa Henry
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引用次数: 12

Abstract

INTRODUCTION: Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases. METHODS: We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD. RESULTS: We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic. DISCUSSION: These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging.

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甲型流感病毒感染损害斑马鱼骨骼肌并加剧斑马鱼杜氏肌营养不良模型的疾病
遗传和感染性疾病均可导致骨骼肌退化、炎症、疼痛和/或虚弱。杜氏肌营养不良症(DMD)是最常见的先天性肌肉疾病。由于肌营养不良蛋白的突变,DMD引起进行性肌肉萎缩。甲型和乙型流感病毒常与肌肉并发症有关,尤其是儿童。感染可激活免疫反应,免疫抑制药物可减轻DMD症状。这些数据表明免疫系统可能导致肌肉病理。然而,免疫反应在DMD和流感肌肉并发症中的作用尚不清楚。dmd突变斑马鱼是研究dmd病理分子和细胞机制的良好模型。我们最近发现斑马鱼可以感染人类流感病毒(IAV)。因此,斑马鱼是一个强大的系统,可以用来询问有关遗传和/或传染病引起的肌肉损伤的病因和机制的问题。方法:我们用IAV感染斑马鱼,并检测肌肉组织结构、肌膜完整性、细胞-细胞外基质(ECM)附着以及IAV单独感染或DMD背景下炎症的分子和细胞标志物。结果:我们发现iav感染的斑马鱼表现为轻度肌肉变性,伴有肌膜损伤和ECM粘连受损。在iav感染的斑马鱼肌肉中引发先天免疫反应:NFkB信号被激活,促炎细胞因子表达上调,中性粒细胞定位于肌肉损伤部位。IAV感染的dmd突变体表现出比预期的dmd突变和IAV感染的加性效应更严重的肌肉损伤,这表明肌营养不良蛋白缺乏和IAV感染引起的肌肉损伤是协同的。讨论:这些数据证明了在患有遗传性肌肉疾病的个体中预防IAV感染的重要性。阐明免疫介导的肌肉损伤机制不仅适用于DMD和IAV,也适用于其他已知受免疫系统、炎症和肌肉组织影响的疾病,如自身免疫性疾病、癌症和衰老。
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