The Role of Schwann Cell Lipid Droplets In Neuropathology of Leprosy

雪旺细胞脂滴在麻风病神经病理学中的作用

• 批准号: 10651645
• 负责人: John T Belisle
• 金额: $ 56.45万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651645
• 关键词: Address; Affect; Annual Reports; Axon; Bacillus; Bacteria; Bacterial Infections; Binding; Biochemical; Biological; Brazil; Case Study; Catabolism; Cells; Cellular Metabolic Process; Cholesterol; Cholesterol Homeostasis; Chronic Granulomatous Disease; Country; Cytochrome P450; Deformity; Demyelinations; Detection; Diagnosis; Discrimination; Disease; Dystroglycan; Enzymes; Epidemiology; Equilibrium; Etiology; Event; Fiber; Fibrosis; Functional disorder; Generations; Growth; Homeostasis; Human; Impairment; India; Infection; Innate Immune Response; Intervention; Leprosy; Ligands; Lipids; Metabolism; Molecular; Mycobacterium leprae; Myelin; Myelin Sheath; NADH; NADP; Nerve; Nerve Fibers; Neurons; Neuropathogenesis; Neuropathy; Oxidoreductase; PPAR gamma; Pathogenesis; Pathogenicity; Patients; Peripheral; Peripheral Nerves; Pharmacotherapy; Play; Population; Prevalence; Production; Proliferating; Proteins; Public Health; Receptor Cell; Reporting; Research; Role; Schwann Cells; Signal Transduction; Surface; Symptoms; TLR6 gene; Temperature Sense; Testing; Touch sensation; Tropism; cell envelope; global health; in vivo; inhibitor; laminin alpha 2; lipid metabolism; lipidomics; mannose receptor; myelination; nerve damage; neural; neuropathology; novel; oxidation; pathogen; permissiveness; physically handicapped; prevent; receptor; therapy development; transcription factor; transmission process

Summary Leprosy is no longer designated as a global health problem by the WHO (defined by a registered prevalence of less than one case of leprosy per 10,000 population); however, about 200,000 new cases are still reported each year. Recently several epidemiological reports based on “find-and-treat” campaigns have indicated under reporting and suggested “hidden-leprosy”. This, as well as the identification of environmental reservoirs, would explain the continued transmission of the etiological agent, Mycobacterium leprae, in the human population. The most pronounced forms of this disease manifest with sever deformities and physical disabilities that are a result of irreversible nerve damage caused by the pathogen's tropism for peripheral nerves. Specifically, M. leprae has evolved and adapted to infect and survive in Schwann cells (SCs), where defined host-pathogen interactions result in demyelination and nerve fibrosis. The molecular and biochemical interactions of M. leprae and SCs have not been well defined. Thus, elucidating these interactions and their downstream consequences is essential to understand the neuropathogenesis of leprosy and to develop appropriate interventions. The ability of M. leprae to induce lipid droplet formation in SCs has been established as key and fundamental aspect of M. leprae pathogenicity. As such, the focus of the proposed research is to define the molecular interactions that result in lipid droplet formation by M. leprae infected SCs and understand how M. leprae utilizes lipids from these droplets to support its growth and drive pathogenesis. These objectives are based on the unifying hypothesis that, via surface ligands M. leprae gains access to SCs and induces lipid droplet formation. The pathogen modulation of host cell lipid metabolism promotes SC dysfunction and the generation of a permissive innate immune response that facilitates bacilli persistence in the nerve. Further, M. leprae catabolism of the lipid droplet associated cholesterol supports the pathogens intracellular growth, as well as drives cell signaling events that result in impairment of myelin production and stability.

总结 麻风病不再被世界卫生组织指定为全球性健康问题（定义为登记患病率为 每10，000人中不到1例麻风病）;但是，每年仍报告约200，000例新病例， 年最近，基于“发现和治疗”运动的几份流行病学报告表明， 报告并提出“隐性麻风病”。这一点，以及环境水库的确定， 解释麻风分枝杆菌在人群中的持续传播。的 这种疾病的最显著形式表现为严重的畸形和身体残疾， 病原体对周围神经的嗜性导致的不可逆的神经损伤。具体来说，M。麻风病人有 进化并适应感染并在雪旺细胞（SC）中存活，其中定义了宿主-病原体相互作用 导致脱髓鞘和神经纤维化。研究了M.麻风和SC 还没有很好的定义。因此，阐明这些相互作用及其下游后果是至关重要的 了解麻风的神经发病机制，并制定适当的干预措施。M的能力。麻风 诱导SC形成脂滴是M.麻风 致病性因此，拟议研究的重点是定义导致 脂滴形成由M.了解M.麻风病人利用这些液滴中的脂质 以支持其生长并驱动发病机制。这些目标是基于统一的假设，通过 表面配体M.麻风病获得对SC的接近并诱导脂滴形成。病原体调节 宿主细胞脂质代谢促进SC功能障碍和容许性先天免疫应答的产生 促进细菌在神经中的持久存在此外，M。脂滴相关的麻风性皮肤炎 胆固醇支持病原体的细胞内生长，并驱动细胞信号传导事件， 髓鞘产生和稳定性受损。

项目成果

Polyunsaturated Fatty Acid-Derived Lipid Mediators as Potential Biomarkers for Leprosy Among Individuals with Asymptomatic Mycobacterium leprae Infection.

• DOI: 10.1021/acsinfecdis.2c00585
• 发表时间: 2023-08-11
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Silva CAM;Graham BG;Webb K;Islam MN;Harton M;de Mello Marques MA;Marques de Carvalho F;Pinheiro RO;Spencer J;Sarno EN;Batista Pereira GM;Vidal Pessolani MC;Santos de Macedo C;Belisle JT
• 通讯作者: Belisle JT

Effect of Mycobacterium leprae on neurotrophins expression in human Schwann cells and mouse sciatic nerves.

麻风分枝杆菌对人雪旺细胞和小鼠坐骨神经中神经营养蛋白表达的影响。

• DOI: 10.1590/0074-02760200075
• 发表时间: 2020
• 期刊: Memorias do Instituto Oswaldo Cruz
• 影响因子: 2.8
• 作者: Nogueira,MariaRenataSales;Amôr,NádiaGhinelli;Michellin,LetíciaBaccaro;CuryFilho,Milton;Rosa,PatríciaSammarco;Latini,AnaCarlaPereira;Rodrigues,LucianaSilva;Lemes,RoberthaMarianaRodrigues;Lara,FlavioAlves;Pessolani,MariaCrist
• 通讯作者: Pessolani,MariaCrist

Reduction of host cell mitochondrial activity as Mycobacterium leprae's strategy to evade host innate immunity.

• DOI: 10.1111/imr.12962
• 发表时间: 2021-05
• 期刊: Immunological reviews
• 影响因子: 8.7