Interaction of Schistosomiasis mansoni and hepatitis B virus infections on hepatocellular carcinoma

曼氏血吸虫病和乙型肝炎病毒感染对肝细胞癌的相互作用

• 批准号: 10689175
• 负责人: David L Thomas
• 金额: $ 35.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689175
• 关键词: Advocate; Affect; Africa; Africa South of the Sahara; African; Aftercare; Age; Animal Model; Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Etiology; Chronic; Chronic Care; Chronic Hepatitis B; Circulation; Clinical; Collaborations; Country; DNA Double Strand Break; Data; Eligibility Determination; Genes; Genetic; Goals; HBV Genotype; HIV; HIV Infections; Hepatic; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis C virus; Hepatocyte; Human; Human Herpesvirus 4; Human Herpesvirus 8; Human Papillomavirus; Immune response; Immunity; Immunologics; Immunology; In Vitro; Income; Infection; Inflammation; Inflammatory; Interruption; Investigation; JUN gene; Light; Liver; Macrophage; Malignant Neoplasms; Measures; Medical; Mentors; Mesentery; Oncogenes; Oncogenic; Pathway interactions; Patients; Persons; Physiological; Plasma; Praziquantel; Primary carcinoma of the liver cells; Proto-Oncogenes; Public Health; Research; Residual state; Risk; Risk Factors; Schistosoma mansoni; Schistosoma mansonii infection; Senegal; Site; System; T cell response; Testing; Time; Tissues; Treatment Efficacy; Uganda; Universities; Venous; Virus Diseases; Virus Replication; carcinogenicity; chronic infection; cytokine; egg; improved; inflammatory milieu; insight; liver biopsy; mortality; novel; response; standard of care; viral DNA

Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa, and as patients with HIV live longer, the HCC burden may increase. In prior studies, our team identified chronic infection with hepatitis B and C viruses (HBV, HCV), HIV and Schistosomiasis mansoni (Sm) as independent risk factors for HCC. Compared to the US, HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of only months. Proposed is an East and West African partnership between colleagues at Makerere University in Uganda, Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellular carcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research, mentoring and clinical activities in both countries, our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatments to interrupt or reverse the impact of HCC-causing infections. To understand our data demonstrating synergistic interaction between chronic HBV and Sm infections, we will examine HBV clinical and immunological responses in the periphery and the liver in response to Sm treatment with praziquantel. Over time, liver Sm-related inflammation transitions from a Th1 to Th2 bias, and we hypothesize this transition may promote HBV replication. We will evaluate the dynamics of plasma HBV DNA during Sm treatment and correlate these with contemporaneous changes in plasma cytokines to characterize Th1 shifted inflammation. We also concurrently examine HBV specific CD4+ and CD8+ T cell responses, and measures of Sm treatment efficacy. Through investigation of liver biopsies on patients before and after SM treatment as well as with HCC, we anticipate confirming in humans that Sm is pro-carcinogenic and that Sm treatment only partially diminishes expression of pro-carcinogenic genes. HIV will be evaluated as a modifier of each relationship. Given our strong record, the proposed research has a high likelihood for successful contribution to reducing the burden and improving understanding of chronic infections and HCC in Africa.

肝细胞癌 (HCC) 是非洲一种非常常见且致命的癌症，随着艾滋病毒患者的生存 时间越长，HCC 负担可能会增加。在之前的研究中，我们的团队发现了乙型肝炎的慢性感染 C 病毒（HBV、HCV）、HIV 和曼氏血吸虫病 (Sm) 作为 HCC 的独立危险因素。 与美国相比，撒哈拉以南非洲地区的 HCC 发病年龄更小、进展期更晚。 只能存活几个月。提议在马凯雷雷同事之间建立东非和西非伙伴关系 乌干达大学、塞内加尔范恩大学和约翰霍普金斯大学专注于艾滋病毒和 非洲肝细胞癌 (HCC)：H2A 联盟。建立在长期合作的基础上 在两国开展研究、指导和临床活动，我们的首要目标是减轻沉重的负担 撒哈拉以南非洲地区 HCC 的发病率。我们主张使用适当的方法来研究癌症拦截策略 中断或逆转 HCC 感染影响的药物治疗。了解我们的数据 证明慢性 HBV 和 Sm 感染之间的协同相互作用，我们将检查 HBV 临床 以及外周和肝脏对吡喹酮 Sm 治疗的免疫反应。 随着时间的推移，肝脏 Sm 相关炎症从 Th1 偏向 Th2 偏向转变，我们假设这种转变 可能促进 HBV 复制。我们将评估 Sm 治疗期间血浆 HBV DNA 的动态，并 将这些与血浆细胞因子的同期变化联系起来，以表征 Th1 转移的炎症。 我们还同时检查 HBV 特异性 CD4+ 和 CD8+ T 细胞反应以及 Sm 治疗措施 功效。通过对 SM 治疗前后患者以及 HCC 患者的肝活检进行调查， 我们预计在人类中证实 Sm 具有致癌性，并且 Sm 治疗仅部分减少 促癌基因的表达。 HIV 将被评估为每种关系的调节因素。鉴于我们的 良好的记录，拟议的研究很有可能成功地减轻负担 提高对非洲慢性感染和肝癌的了解。