Friday, April 19, 2024
4/19/2024
¿ 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.
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