Pyroptosis maintains the integrity of a granuloma

焦亡维持肉芽肿的完整性

• 批准号: 10887377
• 负责人: Edward A Miao
• 金额: $ 6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10887377
• 关键词: Abscess; Antigen-Antibody Complex; Bacteria; Bacterial Infections; Biological Models; Biology; C57BL/6 Mouse; CASP1 gene; CASP4 gene; Caspase; Cd68; Cell Death; Cells; Chromobacterium; Chromosome Mapping; Collagen; Complex; DNA; Deposition; Disease; Fibroblasts; Foreign Bodies; Goals; Grant; Granuloma; Granulomatous; Hepatocyte; Homeostasis; Immune; Immune response; Immune system; Immunologic Stimulation; Infection; Infectious Agent; Invaded; Kupffer Cells; Laboratory mice; Lesion; Liver; Macrophage; Modeling; Molecular; Mus; NOS2A gene; Necrosis; Organ; Pathology; Process; Stains; Stimulus; Structure; Susceptibility Gene; T-Lymphocyte; Thick; Tissues; Tuberculosis; Virulence; adaptive immune response; bactericide; cell type; innovation; microbial; mouse model; neutrophil; novel; pathogen; prevent; recruit; response; trait

Granulomas are complex immunologic structures formed in tissues in response to infection. The general function of a granuloma has been elusive because many infections that stimulate granuloma responses do not resolve. Often, granulomas are described as immunologic responses that wall off an infectious agent that cannot be cleared by the immune system. Basic understandings of the fundamentals of a granuloma have been elusive because mouse models where granulomas form are rare or complicated. We have discovered a novel bacterial infection model where the murine immune system forms a granuloma. When mice are infected by Chromobacterium violaceum, the immunologic response fails to clear the bacterium from the liver within the first several days. Then a granuloma forms around the infected lesion, and this complex immunologic response successfully sterilizes the infection and returns the organ to homeostasis typically within 7-14 days post infection. Therefore, we have discovered a novel infectious model where basic granuloma biology can be elucidated. C. violaceum first infects hepatocytes and perhaps Kupffer cells in the liver. This rapidly stimulates a neutrophil swarm within the first day post infection. However, the neutrophil swarm fails to eradicate the infection, and the neutrophils themselves appear to become replicative intracellular niches for the bacterium. Three days post infection the neutrophil swarm dies and forms a central necrotic core of the lesion. Macrophages begin to appear at the periphery of the lesion at 3 days post infection and form a thick macrophage zone that surrounds the necrotic core by day 5-7. Thereafter, the bacteria are killed through the action of inducible nitric oxide synthase, the granuloma is sterilized, and shrinks over the next week. Granuloma burdens are sterilized between 7-21 days post infection. This all occurs in the absence of T cells or other adaptive immune cells. In this grant, we use this novel granuloma model to explore the importance of pyroptotic cell death in the granuloma.

肉芽肿是组织中响应感染而形成的复杂免疫结构。肉芽肿的一般功能是难以捉摸的，因为许多刺激肉芽肿反应的感染不会消退。通常，肉芽肿被描述为免疫反应，其将不能被免疫系统清除的感染因子隔离。对肉芽肿的基本原理的基本理解一直是难以捉摸的，因为肉芽肿形成的小鼠模型是罕见的或复杂的。我们发现了一种新的细菌感染模型，其中小鼠免疫系统形成肉芽肿。当小鼠被紫色色杆菌感染时，免疫反应无法在最初几天内将细菌从肝脏中清除。然后在感染的病变周围形成肉芽肿，这种复杂的免疫反应成功地使感染绝育，并通常在感染后7-14天内使器官恢复稳态。因此，我们发现了一种新的感染模型，其中基本的肉芽肿生物学可以阐明。C.紫色菌首先感染肝细胞，可能还感染肝脏中的枯否细胞。这在感染后的第一天内迅速刺激嗜中性粒细胞群。然而，嗜中性粒细胞群不能根除感染，并且嗜中性粒细胞本身似乎成为细菌的复制细胞内小生境。感染后三天，中性粒细胞群死亡并形成病变的中央坏死核心。感染后3天，巨噬细胞开始出现在病变的外周，并在第5-7天形成围绕坏死核心的厚巨噬细胞区。此后，细菌通过诱导型一氧化氮合酶的作用被杀死，肉芽肿被消毒，并在接下来的一周内缩小。肉芽肿负荷在感染后7-21天之间灭菌。这一切都发生在缺乏T细胞或其他适应性免疫细胞的情况下。在这项资助中，我们使用这种新型肉芽肿模型来探索肉芽肿中火性细胞死亡的重要性。