Acquired deficiency of innate immunity (ficolin-2) among elderly adults

老年人获得性先天免疫（ficolin-2）缺陷

• 批准号: 9269959
• 负责人: Moon H. Nahm
• 金额: $ 31.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269959
• 关键词: Adult; Aging; Antigens; Apoptotic; Archives; Binding; Biological; Biological Process; Biology; Blood Circulation; Cancer Patient; Caring; Cell Death; Cells; Child; Clinical; Complement; Complement Activation; Deposition; Disease; Elderly; Encapsulated; Epidemiology; Excision; Gram-Positive Bacteria; Individual; Infection; Inflammation; Lectin; Ligands; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medical; Medicine; Mitochondria; Molecular; Natural Immunity; Nature; Opsonin; Outcome; Pathway interactions; Patients; Peptide Sequence Determination; Peptides; Persons; Pneumococcal Infections; Pneumonia; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Predisposition; Prevalence; Process; Role; Sampling; Serological; Serotyping; Serum; Serum Proteins; Solid Neoplasm; Streptococcus pneumoniae; Testing; Universities; Vaccinated; Virulence; Western Blotting; base; capsule; clinically significant; complement pathway; complement system; experience; ficolin; ficolin-beta; human old age (65+); immune function; immunogenicity; immunosenescence; inhibitor/antagonist; insight; novel; older patient; pathogen; public health relevance; response; young adult

 DESCRIPTION (provided by applicant): Streptococcus pneumoniae (pneumococcus) is known for causing pneumonia and invasive pneumococcal diseases (IPDs), which are often lethal among elderly adults. Its virulence is mainly due to its expression of one of more than 90 serologically distinct polysaccharide (PS) capsules (i.e., serotypes). Most pneumococcal serotypes cause IPDs in both young children and elderly adults; however, for unknown reasons, pneumococci expressing the serotype 11A capsule cause IPDs almost exclusively in elderly adults or patients with cancer. We have shown that ficolin-2 (L-ficolin), which can trigger the lectin pathway of the complement- activation cascade, deposits complement on 11A pneumococci, providing a natural protection against serotype 11A IPDs in young persons. We also found that the sera of many elderly (but not young) adults have ficolin-2 inhibitors and ligands. Since ficolin-2 can bind host apoptotic cells and mitochondria as well as pathogens, host cell fragments found in elderly and cancer patients may bind and inhibit ficolin-2. In addition, ficolin-2 inhibitors would reduce complement activation by the pneumococcal PS vaccine (PPV23), which contains 23 PSs including the 11A PS, and may thus reduce the immunogenicity to PPV23. To explain the presence of ficolin-2 inhibitors among the elderly, we have hypothesized that many elderly adults and cancer patients have host cell fragments in the circulation that bind and inhibit ficolin-2, reduce the immunogenicity of PPV23, and reduce hosts' survival. To examine this hypothesis, we will A) Determine the epidemiology of ficolin-2 inhibitors using archived and fresh sera from elderly adults and cancer patients; B) Investigate the effects of ficolin-2 inhibitors on clinical outcomes in elderly adults by (i) investigating the inhibitors' abilities to interfere with other lectin- pathway activators, (ii) their correlations wth other aging-associated parameters, and (iii) their responses to PPV23; and C) Identify the molecular nature of ficolin-2 inhibitors as ficolin-2 ligands with western blotting and mass spectrometry. Our studies will be greatly facilitated because of our prior experience in micro-scale purification and peptide sequencing of serum proteins and because of the availability of sera and information from an on-going 10-year study of the elderly at our university. Although ficolin-2 binds numerous pathogens and host cell fragments, its roles in inflammation and infections are relatively unknown due to its recent discovery. Identification of the inhibitors' molecular nature will provide mechanistic insights into this novel acquired deficiency of innate immunity common among the elderly. By enhancing our understanding of the aging-associated increase in infection susceptibility and decline of the immune function, our proposed studies are directly relevant to the medical care of the elderly. Additionally, these studies will also have a broad relevance and impact on biology in general because ficolin-2 is an evolutionarily ancient molecule that has likely been integrated into many fundamental biologic processes.

 描述（由申请人提供）：已知肺炎链球菌（肺炎球菌）可引起肺炎和侵袭性肺炎球菌疾病（IPD），这些疾病在老年人中通常是致命的，其毒力主要是由于其表达 90 多种血清学上不同的多糖之一。 (PS) 胶囊（即血清型）。大多数肺炎球菌血清型引起。幼儿和老年人均会出现 IPD；然而，由于未知原因，表达血清型 11A 胶囊的肺炎球菌几乎只在老年人或癌症患者中引起 IPD。我们已经证明，ficolin-2（L-ficolin）可引发 IPD。补体激活级联的凝集素途径将补体沉积在 11A 肺炎球菌上，为年轻人提供针对血清型 11A IPD 的天然保护。还发现许多老年人（但不是年轻人）的血清含有 ficolin-2 抑制剂和配体，由于 ficolin-2 可以结合宿主凋亡细胞和线粒体以及病原体，因此在老年人和癌症患者中发现的宿主细胞碎片可能会结合并结合。此外，ficolin-2 抑制剂会减少肺炎球菌 PS 疫苗 (PPV23) 的补体激活，该疫苗含有 23 个 PS，包括 11A PS，并且可能会抑制补体激活。从而降低PPV23的免疫原性 为了解释老年人中ficolin-2抑制剂的存在，我们发现许多老年人和癌症患者的循环中存在结合并抑制ficolin-2的宿主细胞片段，降低了PPV23的免疫原性。 ，并降低宿主的存活率，我们将 A) 使用老年人和癌症患者的存档和新鲜血清确定 ficolin-2 抑制剂的流行病学；通过 (i) 调查 ficolin-2 抑制剂对老年人临床结果的影响 抑制剂干扰其他凝集素途径激活剂的能力，(ii) 它们与其他衰老相关参数的相关性，以及 (iii) 它们对 PPV23 的反应；以及 C) 鉴定 ficolin-2 抑制剂作为 ficolin-2 配体的分子性质由于我们之前在血清蛋白的微量纯化和肽测序方面的经验以及来自血清和信息的可用性，我们的研究将大大方便。我们大学正在进行一项针对老年人的为期 10 年的研究，尽管 ficolin-2 可以结合多种病原体和宿主细胞碎片，但由于其最近的发现，其在炎症和感染中的作用相对未知。通过增强我们对与衰老相关的感染易感性增加和免疫功能下降的认识，我们提出的研究与老年人的医疗保健直接相关。 ， 这些研究还将对生物学产生广泛的相关性和影响，因为 ficolin-2 是一种进化上古老的分子，很可能已融入许多基本的生物过程。