Targeting parasite-host communication to combat liver fluke-induced bile duct cancer

针对寄生虫与宿主的通讯来对抗肝吸虫诱发的胆管癌

• 批准号: 10453668
• 负责人: Paul J Brindley
• 金额: $ 32.69万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453668
• 关键词: Address; Adolescent; Adult; Age; Antibodies; Antigens; Automobile Driving; Bile Duct Epithelium; Bile duct carcinoma; Biliary; Biogenesis; CRISPR/Cas technology; Cancer Vaccines; Carcinogens; Cell Line; Cell Proliferation; Cell secretion; Cells; Cessation of life; Chimera organism; Cholangiocarcinoma; Chronic; Communication; Complement; Country; Development; Disease; Eastern Europe; Epithelial; Epithelial Cells; Event; Far East; Fasciola hepatica; Food; Genes; Growth; Growth Factor; Hamsters; Helminths; Hepatobiliary; Homeostasis; Human; Immune response; In Vitro; Incidence; Infection; Inflammatory; Interleukin-6; International Agency for Research on Cancer; Knock-out; Laos; Larva; Light; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mechanics; Mediator of activation protein; Modeling; Molecular; Mutation; Neoplasms; Nitrosamines; Opisthorchiasis; Opisthorchis; Opisthorchis viverrini; Organoids; Parasites; Parasitic infection; Pathogenesis; Pathogenicity; Pathology; Persons; Phenotype; Process; Production; Prognosis; Proteins; Province; Public Health; RNA Interference; Recombinants; Reporting; Risk Factors; Rivers; Rodent Model; Role; Signal Transduction; Standardization; Surface; THBS1 gene; Testing; Thailand; Trematoda; Vaccination; Vaccines; Vesicle; World Health Organization; angiogenesis; anti-cancer; bile duct; biliary tract; cancer therapy; carcinogenesis; carcinogenicity; cell growth; cell motility; cholangiocyte; combat; cytokine; dietary; exosome; extracellular vesicles; foodborne; genetic manipulation; genome editing; granulin; in vivo; innovation; irritation; migration; pathogen; protective efficacy; secretory protein; tumorigenic; uptake; vaccine development; wound healing

Targeting parasite-host communication to combat liver fluke-induced bile duct cancer PROJECT SUMMARY Liver fluke infection with Opisthorchis viverrini remains problematic in East Asia and is endemic in Thailand and Laos, where ~10 million people are infected. The public health implications of this situation are substantial since there is no stronger link between a human malignancy and a eukaryotic pathogen than that between cholangiocarcinoma (CCA) (bile duct cancer) and infection with the liver fluke O. viverrini. Northeast Thailand reports the highest incidence of CCA worldwide, with the 2014 CCA age standardized incidence rate (ASR) of 85 per 100,000, which equates to 26, 000 CCA-related deaths annually. The contrast to countries without liver flukes is stark given that incidence of CCA is less than 3 per 100,000 elsewhere (USA, 1.67 ASR in 2014). To survive in hostile environs of the host biliary tract, the liver fluke excretes/secretes (ES) proteins and extracellular vesicles (EVs) for host-parasite communication, to manipulate the host responses, and to modify homeostasis, changes conducive to malignant transformation. This proposal targets components of liver fluke ES that drive the phenotypic hallmarks of cancer in the biliary tract: the growth mediator granulin, Ov-GRN-1 and extracellular vesicles (EVs) and their vesicle surface tetraspanins (TSPs). These mediators enter biliary epithelial cells, inducing proliferation, migration, angiogenesis, wound healing and proinflammatory cytokine IL- 6 production. We hypothesize that blocking internalization of Ov-GRN-1 and/or EVs into cholangiocytes will disrupt host-parasite communication, and in turn malignant transformation. We aim to test this hypothesis with the three specific aims. Aim 1. Assess the impact of using CRISPR-Cas9 to knock out liver fluke Ov-grn-1 and Ov-tsp genes on in vitro surrogates of pathogenicity and neoplasia. Aim 2. Characterize pathogenesis and cholangio-carcinogenicity of infection with gene edited (knockout) parasites in an informative rodent model of liver fluke infection and infection-induced bile duct cancer. Aim 3. Determine whether subunit Ov-GRN-1 and EV TSP vaccines protect against liver fluke infection and infection-induced cancer, and address mechanisms by which functional antibodies minimize pathology. We will utilize is a model of cholangiocarcinogenesis in which liver fluke infection is the confirmed risk factor. Innovations of the proposal include editing of the genome of the liver fluke using CRISPR-Cas9, targeting Ov-GRN-1 and EV surface tetraspanins with antibodies as an approach to anti-cancer therapy, and combining the findings of these innovations to develop a vaccine to block liver fluke infection. Fluke proteins that communicate at the host-parasite interface likely represent an Achilles' heel, and so targeting fluke-host communication in the form of an anti-fluke/ anti-cancer vaccine may ultimately defeat the disease. !

靶向寄生虫 - 宿主通信以对抗肝fluke诱导的胆管癌 项目摘要 肝氟通过Opisthorchis Viverrini感染在东亚仍然有问题，在泰国是特有的 老挝，约有1000万人被感染。这种情况的公共卫生影响很大 由于人类恶性肿瘤与真核病原体之间没有更强的联系 胆管癌（CCA）（胆管癌）和肝氟氟尼氏菌感染。泰国东北部 报告全球CCA的发病率最高，2014年CCA年龄标准化发病率（ASR） 每100,000人为85，每年26,000次与CCA相关的死亡。与没有肝脏的国家形成鲜明对比 鉴于CCA的发病率在其他地方的每100,000次（美国，2014年1.67 ASR）少于每100,000的发病率，因此Flukes是明显的。 为了在宿主胆道的敌对环境中生存，肝氟排泄/分泌（ES）蛋白质和 细胞外囊泡（EV）用于宿主 - 寄生虫通信，操纵宿主反应并修改 稳态，变化有利于恶性转化。该提议针对肝氟的组成部分 ES驱动胆道中癌症的表型标志：生长介质颗粒，OV-GRN-1 和细胞外囊泡（EV）及其囊泡表面四翼烷（TSP）。这些调解人进入胆道 上皮细胞，诱导增殖，迁移，血管生成，伤口愈合和促炎细胞因子IL- 6生产。我们假设将OV-GRN-1和/或电动汽车的内在化阻止到胆管细胞中 破坏宿主 - 寄生虫交流，进而破坏恶性转化。我们旨在通过 三个特定的目标。目标1。评估使用CRISPR-CAS9敲除肝fluke ov-grn-1和 OV-TSP基因的致病性和肿瘤替代物。 AIM 2。表征发病机理和 用基因编辑（基因敲除）寄生虫感染的胆管癌 - 在内容丰富的啮齿动物模型中 肝炎感染和感染引起的胆管癌。目标3。确定亚基OV-grn-1和 EV TSP疫苗可预防肝氟化物感染和感染诱导的癌症，并解决机制 通过哪种功能抗体最小化病理。我们将利用是一种胆管癌的模型 哪种肝氟化物感染是确认的危险因素。该提案的创新包括基因组的编辑 使用CRISPR-CAS9的肝氟，靶向OV-GRN-1和EV表面四翼烷蛋白，抗体作为一种 抗癌疗法的方法，并结合了这些创新的发现以开发疫苗以阻止 肝炎感染。在宿主寄生虫界面上通信的氟蛋白可能代表阿喀琉斯 鞋跟，因此最终以抗Fluke/抗癌疫苗的形式瞄准Fluke-Host通讯 击败疾病。 呢

项目成果

Rapid assessment of Opisthorchis viverrini IgG antibody in serum: A potential diagnostic biomarker to predict risk of cholangiocarcinoma in regions endemic for opisthorchiasis.

• DOI: 10.1016/j.ijid.2021.12.347
• 发表时间: 2022-03
• 期刊: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
• 影响因子: 8.4
• 作者: Rodpai, Rutchanee;Luvira, Vor;Sadaow, Lakkhana;Sukeepaisarnjaroen, Wattana;Kitkhuandee, Amnat;Paonariang, Krisada;Sanpool, Oranuch;Ittiprasert, Wannaporn;Mann, Victoria H.;Intapan, Pewpan M.;Brindley, Paul J.;Maleewong, Wanchai
• 通讯作者: Maleewong, Wanchai

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype.

• DOI: 10.1093/infdis/jiv291
• 发表时间: 2015-11-15
• 期刊: The Journal of infectious diseases
• 作者: Chaiyadet S;Sotillo J;Smout M;Cantacessi C;Jones MK;Johnson MS;Turnbull L;Whitchurch CB;Potriquet J;Laohaviroj M;Mulvenna J;Brindley PJ;Bethony JM;Laha T;Sripa B;Loukas A
• 通讯作者: Loukas A

Comparative assessment of immunochromatographic test kits using somatic antigens from adult Opisthorchis viverrini and IgG and IgG4 conjugates for serodiagnosis of human opisthorchiasis.

• DOI: 10.1007/s00436-021-07224-6
• 发表时间: 2021-08
• 期刊: Parasitology research
• 影响因子: 2
• 作者: Phupiewkham W;Sadaow L;Sanpool O;Rodpai R;Yamasaki H;Ittiprasert W;Mann VH;Brindley PJ;Maleewong W;Intapan PM
• 通讯作者: Intapan PM

Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production.

• DOI: 10.1016/j.ijpara.2015.06.001
• 发表时间: 2015-10
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Chaiyadet S;Smout M;Johnson M;Whitchurch C;Turnbull L;Kaewkes S;Sotillo J;Loukas A;Sripa B
• 通讯作者: Sripa B

Will COVID-19 become the next neglected tropical disease?

• DOI: 10.1371/journal.pntd.0008271
• 发表时间: 2020-04-01
• 期刊: PLOS NEGLECTED TROPICAL DISEASES
• 影响因子: 3.8
• 作者: Hotez, Peter J.;Bottazzi, Maria E.;Kamhawi, Shaden
• 通讯作者: Kamhawi, Shaden