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Monoclonal antibodies for diagnosis and prophylaxis of invasive Aspergillosis.

机译：用于诊断和预防侵袭性曲霉病的单克隆抗体。

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摘要

Aspergillus fumigatus is a saprophytic fungus that is the primary etiologic agent causing invasive aspergillosis (IA), a deadly mold disease that affects patients with severely compromised immune systems. Two major clinical challenges are timely and accurate diagnosis, and adequate therapeutic agents.;Early diagnosis of IA is associated with improved patient outcome. We sought to develop a monoclonal antibody-based (MAb) diagnostic platform for more sensitive early detection assays. Our work focused on exploiting the lack of study of protein antigens as biomarkers. We used a bottom-up protein-profiling strategy to analyze blood and lung fluids from mice with IA and fungal asthma for proteins unique to IA. We were unable to identify A. fumigatus proteins in mice, and subsequently began working with human BALF as part of an ongoing prospective study. We have identified and confirmed at least six A. fumigatus proteins in a patient with probable IA. Currently these proteins are being evaluated as potential biomarkers for IA.;Treatment or prophylaxis with currently available antifungal agents is often inadequate, as mortality remains high despite therapeutic intervention. A. fumigatus germination in the absence of host immunity is required for establishing invasive disease. Therefore, we used vaccination with whole A. fumtigatus conidia to make a germination-inhibitory IgM, MAb 318. MAb 318 prophylaxis of neutropenic mice administered as repeated intranasal injection prior to lethal challenge, resulted in 60% survival and reduced lung fungal burden. In vitro studies showed that MAb 318 binding to conidia resulted in delayed germination with severely stunted hyphae, and also altered the interaction between alveolar macrophages and conidia. MAb 318 binds to mycelial catalase and two aldehyde dehydrogenases, the latter are 79% identical, but MAb 318 maintained the capacity to inhibit germination in both single and double mutants. We also discovered that these proteins do not compete for MAb 318 binding, and that at least one protein, Aid has binding characteristics similar to the bacterial superantigen protein A. The mechanism underlying MAb 318 protection in mice and in vitro inhibition of germination remains unclear, more exploration is required.
机译：烟曲霉是腐生真菌，是引起侵袭性曲霉病（IA）的主要病原体，侵袭性曲霉病是一种致命的霉菌病，会影响免疫系统严重受损的患者。临床上的两个主要挑战是及时准确的诊断和适当的治疗药物。IA的早期诊断与改善患者预后相关。我们寻求开发一种基于单克隆抗体（MAb）的诊断平台，用于更敏感的早期检测测定。我们的工作集中于利用缺乏对蛋白质抗原作为生物标记物的研究。我们使用了一种自下而上的蛋白质谱分析策略来分析患有IA和真菌性哮喘的小鼠的血液和肺液中IA独特的蛋白。我们无法在小鼠中鉴定出烟曲霉蛋白，随后作为一项正在进行的前瞻性研究的一部分，开始与人BALF一起工作。我们已经确定并确认了可能患有IA的患者中至少有6种烟曲霉蛋白。当前，这些蛋白质被评估为IA的潜在生物标记物。；由于尽管进行了治疗性干预，死亡率仍然很高，但用目前可用的抗真菌剂进行的治疗或预防常常不足。建立宿主性疾病需要在没有宿主免疫力的条件下进行烟曲霉的萌发。因此，我们使用全烟曲霉分生孢子进行疫苗接种，以制作抑制发芽的IgM MAb318。MAb318预防性杀伤前以鼻腔内反复注射的方式预防嗜中性白血球缺乏症的小鼠，可导致60％的存活率并减轻肺部真菌负担。体外研究表明，MAb 318与分生孢子的结合导致发芽延迟，菌丝严重发育不良，并且改变了肺泡巨噬细胞与分生孢子之间的相互作用。 MAb 318与菌丝过氧化氢酶和两种醛脱氢酶结合，后者具有79％的同一性，但MAb 318在单突变体和双突变体中均具有抑制发芽的能力。我们还发现，这些蛋白质无法竞争MAb 318的结合，并且至少一种蛋白质Aid具有与细菌超抗原蛋白A相似的结合特性。目前尚不清楚小鼠中MAb 318保护和体外抑制发芽的潜在机制，需要更多的探索。

著录项

  • 作者

    McCarthy, Jason W.;

  • 作者单位

    Yeshiva University.;

  • 授予单位 Yeshiva University.;
  • 学科 Microbiology.;Botany.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 179 p.
  • 总页数 179
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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