Role of a schistosome cysteine protease in Th response polarization

血吸虫半胱氨酸蛋白酶在 Th 响应极化中的作用

• 批准号: 8721840
• 负责人: Stephen J Davies
• 金额: $ 22.95万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721840
• 关键词: Accounting; Acute; Allergens; Antigens; Bacteria; Bacterial Infections; Basophils; Binding; CD4 Positive T Lymphocytes; Cathepsins B; Chemicals; Chronic; Complex; Conflict (Psychology); Cysteine Protease; Enzymes; Extracellular Space; Goals; HIV; Health Services Accessibility; Helminths; IgE; Immune response; Immune system; Immunity; Infection; Inflammatory; Interleukin-4; Life; Ligands; Malaria; Measurable; Mediating; Modeling; Molecular; Mus; Natural Disasters; Nematoda; Nutrient; Parasites; Pathology; Pattern; Pattern recognition receptor; Peptide Hydrolases; Phenotype; Plants; Platyhelminths; Play; Poverty; Production; Property; Protease Inhibitor; Proteins; Public Health; RNA Interference; Role; Schistosoma; Schistosoma mansoni; Signal Transduction; Source; Staging; T cell response; Techniques; Testing; Toll-like receptors; Virus; Virus Diseases; extracellular; human disease; innovation; mutant; novel strategies; nutrition; pathogen; positional cloning; public health relevance; pyroglyphid; research study; response; social unrest

DESCRIPTION (provided by applicant) Helminths are multicellular pathogens that cause significant human disease in the Developing World, where 2 billion people are infected with helminths of various species. Schistosomes account for 10% of all helminth infections, infecting approximately 200 million people globally. Less complex pathogens, such as bacteria and viruses, express conserved pathogen-associated molecular patterns (PAMPs) that bind host pattern recognition receptors (PRRs, e.g. toll-like receptors (TLRs)) and induce pro-inflammatory CD4+ T helper (Th) 1 responses. In contrast, helminths do not express readily recognizable PAMPs, do not activate classical PRRs and instead induce Th2 and immunomodulatory responses. Indeed, the almost ubiquitous induction of Th2 responses by helminths has led to the hypothesis that Th2 responses evolved as a defense against helminths. Consistent with this hypothesis, there is evidence that Th2 responses can mediate immunological protection against helminth infection and may mitigate the pathology associated with helminth infection. However, the helminth- specific signals that drive Th2 polarization are poorly understood. In some helminths, specific parasite molecules that drive Th2 polarization have been identified, but whether a common underlying mechanism is involved in Th2 induction by helminths in general is unclear. In many helminths, including nematodes and flatworms such as schistosomes, cysteine proteases play a central role in host invasion and acquisition of nutrients and are frequently secreted into the extracellular space to fulfill these roles. Because vertebrate hosts do not normally secrete cysteine proteases but maintain these enzymes under tight control within intracellular compartments, it is hypothesized that the vertebrate immune system has evolved to recognize extracellular cysteine proteases as immunostimulatory pathogen-associated motifs, akin to TLR ligands, but which preferentially induce Th2 rather than Th1 responses. This hypothesis is supported by the observation that cysteine protease activity is also associated with many Th2-inducing allergens, and that cysteine proteases derived from non-helminth sources such as plants also induce Th2 responses. However, direct evidence that helminth cysteine proteases play a role in Th2 response induction during helminth infection is lacking. We recently demonstrated that Schistosoma mansoni cathepsin B1 (SmCB1), a major secreted cysteine protease of S. mansoni, is a dominant antigen during the early stages of schistosome infection and is rapidly targeted by a Th2 response, resulting in production of SmCB1-specific IgE and sensitization of basophils to produce interleukin (IL)-4 in response to schistosome antigens. We therefore hypothesize that SmCB1 is implicated in polarizing the CD4+ T cell response towards a Th2 phenotype during schistosome infection. We propose to test this hypothesis by testing (i) whether SmCB1 protein and its associated protease activity are required for induction of a parasite-specific Th2 response during the early stages of infection, and (ii) whether SmCB1 has intrinsic Th2-inducing properties that are dependent on its protease activity. Our findings may have broad implications for understanding how Th2 responses are induced. Furthermore, as cysteine proteases are readily targeted pharmacologically, our findings may identify novel approaches to modulating Th2 responses during schistosome infection, which might be beneficial in augmenting anti-helminth immunity or mitigating the pathology that is associated with dysregulated Th2 responses.

描述（由申请人提供）蠕虫是在发展中国家引起重大人类疾病的多细胞病原体，其中20亿人感染各种蠕虫。血吸虫占所有蠕虫感染的10%，全球约有2亿人感染。较不复杂的病原体，如细菌和病毒，表达保守的病原体相关分子模式（PAMP），其结合宿主模式识别受体（PRR，例如toll样受体（TLR））并诱导促炎性CD 4 + T辅助细胞（Th）1应答。相反，蠕虫不表达容易识别的PAMP，不激活经典的PRR，而是诱导Th 2和免疫调节反应。事实上，蠕虫对Th 2应答的几乎无处不在的诱导导致了Th 2应答作为对抗蠕虫的防御而进化的假设。与这一假设一致，有证据表明，Th 2应答可以介导针对蠕虫感染的免疫保护，并可能减轻与蠕虫感染相关的病理。然而，驱动Th 2极化的蠕虫特异性信号知之甚少。在一些蠕虫中，驱动Th 2极化的特定寄生虫分子已被确定，但是否有一个共同的潜在机制参与蠕虫的Th 2诱导尚不清楚。 在许多蠕虫中，包括线虫和扁形虫，如寄生虫，半胱氨酸蛋白酶在宿主入侵和营养物质的获取中发挥核心作用，并经常分泌到细胞外空间以履行这些作用。由于脊椎动物宿主通常不分泌半胱氨酸蛋白酶，而是将这些酶维持在细胞内区室的严格控制下，因此假设脊椎动物免疫系统已经进化到将细胞外半胱氨酸蛋白酶识别为免疫刺激性病原体相关基序，类似于TLR配体，但优先诱导Th 2而不是Th 1反应。这一假设得到以下观察结果的支持：半胱氨酸蛋白酶活性也与许多Th 2诱导性变应原相关，并且来源于非蠕虫来源如植物的半胱氨酸蛋白酶也诱导Th 2应答。然而，蠕虫半胱氨酸蛋白酶在蠕虫感染过程中的Th 2应答诱导中发挥作用的直接证据缺乏。 我们最近发现，曼氏血吸虫组织蛋白酶B1（SmCB 1）是曼氏血吸虫主要分泌的半胱氨酸蛋白酶。mansoni）是在溶酶体感染的早期阶段期间的优势抗原，并且被Th 2应答快速靶向，导致SmCB 1特异性IgE的产生和嗜碱性粒细胞的致敏以响应溶酶体抗原产生白细胞介素（IL）-4。因此，我们假设SmCB 1是在极化的CD 4 + T细胞对Th 2表型的反应，在溶酶体感染。我们建议测试这一假设测试（一）是否SmCB 1蛋白及其相关的蛋白酶活性所需的诱导寄生虫特异性Th 2反应在感染的早期阶段，以及（ii）是否SmCB 1具有内在的Th 2诱导特性，这是依赖于其蛋白酶活性。我们的研究结果可能对理解Th 2反应是如何诱导的具有广泛的意义。此外，由于半胱氨酸蛋白酶很容易靶向免疫缺陷病毒，我们的研究结果可能会确定新的方法来调节Th 2反应在寄生虫感染，这可能是有益的，在增强抗蠕虫免疫或减轻病理与失调的Th 2反应。