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

基本信息

批准号：
8444920
负责人：
Stephen J Davies
金额：
$ 18.01万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-16 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444920
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

项目摘要

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）蠕虫是多细胞病原体，在发展中国家中引起重大人类疾病，其中20亿人感染了各种物种的蠕虫。血块占所有蠕虫感染的10％，全球大约2亿人感染了2亿人。较不复杂的病原体，例如细菌和病毒，与结合宿主模式识别受体（PRR，例如Toll-like受体（TLRS））的病原体相关的分子模式（PAMP）表达保守的病原体相关的分子模式（PAMP），并诱导促炎性CD4+ T Helper（TH）1回答。相比之下，蠕虫不表达容易识别的幼虫，不要激活经典的PRR，而是诱导TH2和免疫调节反应。确实，蠕虫几乎无处不在的Th2反应引起了一个假设，即Th2反应反应以防止蠕虫的辩护。与这一假设一致，有证据表明，TH2反应可以介导免疫保护侵害蠕虫感染，并可以减轻与蠕虫感染相关的病理学。然而，驱动Th2极化的蠕虫率特定信号知之甚少。在某些蠕虫中，已经鉴定出驱动Th2极化的特定寄生虫分子，但是通常尚不清楚蠕虫是否参与Th2诱导的常见潜在机制尚不清楚。在许多蠕虫中，包括线虫和扁虫（如血吸虫）中，半胱氨酸蛋白酶在宿主入侵和获得营养中起着核心作用，并且经常被分泌到细胞外空间中以履行这些角色。因为脊椎动物宿主通常不会分泌半胱氨酸蛋白酶，而是在细胞内室内保持严格控制的这些酶，因此假设脊椎动物免疫系统已经演变为识别细胞外的半胱氨酸蛋白酶作为免疫接触式的致病性致病基序，以下是tlr ligands ass，但诱导TH2而不是Th1响应。这一假设得到了这样一种观察，即半胱氨酸蛋白酶活性也与许多Th2诱导过敏原相关，并且源自非吡啶源（例如植物）的半胱氨酸蛋白酶也诱导了Th2反应。然而，缺乏蠕虫性半胱氨酸蛋白酶在蠕虫感染期间在Th2反应诱导中起作用的直接证据。我们最近证明，Mansoni caltepsin B1（SMCB1）是S. mansoni的主要分泌的半胱氨酸蛋白酶，在血吸虫感染的早期阶段是一种主要的抗原，并由TH2反应迅速靶向，导致SMCB1特异性IGE的产生嗜碱性粒细胞对黑齿抗原产生白介素（IL）-4的敏化。因此，我们假设SMCB1涉及在血块感染期间对CD4+ T细胞对Th2表型的响应的偏振。我们建议通过测试（i）在感染的早期诱导寄生虫特异性的Th2反应，以及（ii）SMCB1是否具有内在的Th2诱导特性，是否需要SMCB1蛋白及其相关蛋白酶活性来检验这一假设。取决于其蛋白酶活性。我们的发现可能对理解如何诱导TH2响应具有广泛的影响。此外，由于在药理学上很容易靶向半胱氨酸蛋白酶，因此我们的发现可能会确定在血块感染期间调节Th2反应的新方法，这可能有益于增强抗顽固的免疫力或减轻与失调TH2反应相关的病理学。