Role of a schistosome cysteine protease in Th response polarization

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，在发展中国家有20亿人感染了不同种类的蠕虫。血吸虫占所有寄生虫感染的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（PAMPs），其结合宿主模式识别受体（PRRs，如toll样受体（TLRs））并诱导促炎CD4+ T辅助（Th） 1反应。相比之下，蠕虫不表达容易识别的PAMPs，不激活经典的PRRs，而是诱导Th2和免疫调节反应。事实上，蠕虫对Th2反应的诱导几乎无处不在，这导致了一种假设，即Th2反应是为了防御蠕虫而进化的。与这一假设相一致，有证据表明Th2反应可以介导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Th2极化的蠕虫特异性信号知之甚少。在一些蠕虫中，已经确定了驱动Th2极化的特定寄生虫分子，但是否有一个共同的潜在机制参与了蠕虫诱导Th2的一般机制尚不清楚。在许多蠕虫中，包括线虫和扁虫，如血吸虫，半胱氨酸蛋白酶在宿主入侵和获取营养物质中起着核心作用，并且经常分泌到细胞外空间来完成这些作用。由于脊椎动物宿主通常不分泌半胱氨酸蛋白酶，而是在细胞内的区室中严格控制这些酶，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病原体相关基序，类似于TLR配体，但优先诱导Th2而不是Th1反应。这一假设得到了观察结果的支持，即半胱氨酸蛋白酶活性也与许多Th2诱导过敏原有关，并且来自非蠕虫来源（如植物）的半胱氨酸蛋白酶也诱导Th2反应。然而，缺乏直接证据表明蠕虫半胱氨酸蛋白酶在蠕虫感染过程中Th2反应诱导中发挥作用。我们最近证明，曼氏血吸虫组织蛋白酶B1 （SmCB1）是曼氏血吸虫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个优势抗原，并被Th2反应迅速靶向，导致SmCB1特异性IgE的产生和嗜碱性细胞的增敏，以产生白细胞介素(IL)-4，以响应血吸虫抗原。因此，我们假设SmCB1参与血吸虫感染期间CD4+ T细胞对Th2表型的极化反应。我们建议通过测试(i) SmCB1蛋白及其相关蛋白酶活性是否需要在感染的早期阶段诱导寄生虫特异性Th2反应，以及（ii） SmCB1是否具有依赖于其蛋白酶活性的内在Th2诱导特性来验证这一假设。我们的发现可能对理解如何诱导Th2反应具有广泛的意义。此外，由于半胱氨酸蛋白酶在药理学上很容易被靶向，我们的研究结果可能会发现在血吸虫感染过程中调节Th2反应的新方法，这可能有助于增强抗蠕虫免疫或减轻与Th2反应失调相关的病理。

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.