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

 描述(申请人提供)：肺炎链球菌(肺炎球菌)是众所周知的肺炎和侵袭性肺炎球菌(IPDS)，这通常是致命的老年人。它的毒力主要是因为它表达了90多种血清学上不同的多糖(PS)胶囊中的一种(即血清型)。大多数肺炎球菌血清型都会引起幼儿和老年人的IPDS；然而，由于未知的原因，表达11A血清型胶囊的肺炎球菌几乎只在老年人或癌症患者中引起IPDS。我们已经证明，能够触发补体活化级联反应的凝集素途径的无花果-2(L-无花果)可以将补体沉积在11A肺炎球菌上，对年轻人的11A型IPDS提供天然的保护。我们还发现，许多老年人(但不是年轻人)的血清中都有无花果-2抑制剂和配体。由于无花果-2可以结合宿主细胞、线粒体和病原体，在老年人和癌症患者中发现的宿主细胞片段可能结合和抑制无花果-2。此外，无花果-2抑制剂会降低肺炎球菌PS疫苗(PPV23)对补体的激活，从而降低对PPV23的免疫原性。PPV23包括11A PS在内的23个PS。为了解释为什么在老年人中存在Ficolin-2抑制剂，我们假设许多老年人和癌症患者的血液循环中都有宿主细胞片段，这些片段结合和抑制Ficlin-2，降低PPV23的免疫原性，从而降低宿主的存活率。为了验证这一假设，我们将A)使用来自老年人和癌症患者的存档和新鲜血清来确定FICLOIN-2抑制剂的流行病学；B)通过(I)调查FICLOIN-2抑制剂对老年患者临床结果的影响 抑制物干扰其他凝集素途径激活物的能力，(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)用Western blotting和MS鉴定FICLINO-2抑制剂的分子性质为FICLOIN-2配体。由于我们以前在血清蛋白的微量纯化和多肽测序方面的经验，以及我们大学正在进行的10年老年人研究的血清和信息的可用性，我们的研究将大大促进我们的研究。虽然无花果-2结合了大量的病原体和宿主细胞片段，但由于最近的发现，它在炎症和感染中的作用相对未知。对抑制物分子性质的鉴定将提供对这种在老年人中常见的获得性先天免疫缺陷的机械性见解。通过加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了解，我们建议的研究与老年人的医疗保健直接相关。此外，这些研究还将对整个生物学产生广泛的相关性和影响，因为无花果-2是一种进化上古老的分子，可能已经整合到许多基本的生物过程中。

 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.