Virally-induced tumorigenesis controlled by the microbiota

由微生物群控制的病毒诱导的肿瘤发生

• 批准号: 10189532
• 负责人: MICHAEL ANDREW FISCHBACH
• 金额: $ 47.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189532
• 关键词: Adaptive Immune System; Address; Animals; B-Lymphocytes; BALB/cJ Mouse; Bacteria; Biological Response Modifiers; Blood-Borne Pathogens; CD8B1 gene; Cancer Model; Characteristics; Chicago; Data; Development; Elements; Environment; Environmental Risk Factor; Epigenetic Process; Escherichia coli; Etiology; Event; Gene Expression Profiling; Genes; Genome; Germ-Free; Gnotobiotic; Goals; Human; Immune response; Immunologic Receptors; Incidence; Insertional Mutagenesis; Lactobacillus; Ligands; Liver; Lymphoma; Malignant Neoplasms; Malignant neoplasm of liver; Mammalian Genetics; Mediating; Monitor; Murine leukemia virus; Mus; Mutation; Oncogene Activation; Oncogenes; Oral; Phenotype; Process; Property; Proto-Oncogenes; Research; Resistance; Retroviridae; Role; Series; Shigella; Somatic Mutation; Spleen; Sterility; System; T cell response; T-Lymphocyte; Technology; Testing; Time; Tumor Escape; Universities; Up-Regulation; Variant; Vertebrates; Viral; Viral Oncogene; Virus Replication; adaptive immune response; anti-cancer; bacterial genetics; cancer immunotherapy; carcinogenesis; cell growth regulation; cell type; colon cancer progression; commensal bacteria; commensal microbes; germ free condition; gut microbes; gut microbiota; interest; leukemia; leukemogenesis; metabolomics; microbial; microbiota; mutant; response; tumor; tumorigenesis; virology

Abstract Retroviruses induce a broad range of tumors in vertebrates. Although some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, their capacity to induce tumors depends on integration near cellular proto-oncogenes. However, oncogene activation alone is not sufficient for tumor induction and additional events are required for tumor development. Murine Leukemia Virus (MuLV), which can spread as an oral and as a blood-borne pathogen, is highly proficient in causing leukemia. Intriguingly, tumor incidence within the same strain of infected mice varies between different facilities. Among environmental factors that may differ between the research labs, the variation in gut microbiota stands out.Thus, we sought to determine whether the microbiota contributes to virally-induced leukemogenesis. Accordingly, we monitored virally-induced leukemia in germ-free (GF, sterile) and specific pathogen free (SPF) conventionally raised BALB/cJ mice. Even though MuLV replication and spread were not affected in the absence of the microbiota, GF mice were significantly more resistant to the leukemia than SPF mice. Colonizing GF mice with a defined group of commensal bacteria (Altered Schaedler’s Flora), or with a single bacterium such as Lactobacillus murinus but not Parabacteroides distasonis or similar to E. coli and shigella (SECS) did not change virus replication but abolished the tumor-resistant phenotype of the colonized mice, indicating that some gut microbes have tumor-promoting properties. At the same time, GF mice lacking adaptive immune system (T and B lymphocytes) developed leukemia at a high rate suggesting that the gut microbes facilitate leukemia promotion by counteracting the adaptive immune response. Gene- expression analysis of the pre-leukemic spleens revealed several negative regulators induced by the microbiota. Among those, the ‘V-set and Ig domain-containing 4’ (VSig4) gene, a known negative regulator of T-cell responses attracted our interest because it was found upregulated in various human cancers. The gut microbiota has been implicated in both progression of cancers of colon and liver (‘local’ influence), as well as in systemic anti-cancer effect by enhancing the effect of anti-cancer immunotherapy. There is also a hint that the microbial environment can influence development of non-virally induced lymphomas. To identify the mechanism(s) by which the gut microbiota promotes leukemia, we will use our expertise in virology, mammalian genetics and gnotobiotic technologies (Dr. Golovkina, University of Chicago) and expertise in bacterial genetics and metabolomics (Dr. Fischbach, Stanford University). The goals of the proposal are: to determine the role of microbially regulated-VSig4 in virally-induced leukemogenesis; to characterize the bacterial compound(s) responsible for virally-induced leukemia development; to determine whether the gut microbiota influences leukemia development in a non-viral model of cancer.

摘要 逆转录病毒可引起脊椎动物的多种肿瘤。尽管一些逆转录病毒携带 在它们的基因组中，绝大多数逆转录病毒不编码这些元件，因此，它们的 诱发肿瘤的能力取决于细胞原癌基因附近的整合。然而，癌基因 单靠激活是不足以诱导肿瘤的，肿瘤的发展还需要额外的事件。 小鼠白血病病毒(MuLV)可作为口腔传播和血液传播的病原体，是高度 精通导致白血病。有趣的是，同一品系感染小鼠的肿瘤发病率各不相同。 在不同的设施之间。在研究实验室之间可能有所不同的环境因素中， 肠道微生物区系的变异尤为突出。因此，我们试图确定微生物区系是否对 病毒诱导的白血病形成。因此，我们监测了病毒诱导的无菌白血病(无菌)。 无特定病原体(SPF)常规饲养的BALB/CJ小鼠。即使MuLV复制和 在没有微生物区系的情况下，扩散不受影响，GF小鼠对 白血病比SPF小鼠。用一组确定的共生细菌(改变的Schaedler‘s)定植GF小鼠 植物)，或与单一细菌，如鼠乳杆菌，但不与副杆菌或类似物 对大肠杆菌和志贺氏菌(SECS)的抗药性没有改变病毒的复制，但取消了对肿瘤的抗药性表型 被定植的小鼠，表明一些肠道微生物具有促肿瘤特性。同时，广发 缺乏适应性免疫系统(T和B淋巴细胞)的小鼠患白血病的几率很高 肠道微生物通过对抗适应性免疫反应促进白血病的发生。基因- 对白血病前期脾的表达分析揭示了几种负性调节因子 微生物区系。其中，‘V-set和Ig结构域包含4’基因(VSig4)是一种已知的负性调节因子 T细胞反应引起了我们的兴趣，因为它在各种人类癌症中被发现上调。 肠道微生物区系与结肠癌和肝癌(“局部”)的进展有关 影响)，以及通过增强抗癌免疫治疗的效果而在全身抗癌作用方面。 也有迹象表明，微生物环境可以影响非病毒诱导的 淋巴瘤。为了确定肠道微生物区系促进白血病的机制(S)，我们将使用我们的 病毒学、哺乳动物遗传学和灵知生物技术方面的专业知识(芝加哥大学Golovina博士) 以及细菌遗传学和代谢组学方面的专业知识(斯坦福大学Fischbach博士)。世界银行的目标是 建议是：确定微生物调控的VSig4在病毒诱导的白血病发生中的作用； 鉴定导致病毒诱导的白血病发生的细菌化合物(S)；确定 肠道微生物区系是否影响非病毒性癌症模型中白血病的发展。