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: 10667586
• 负责人: MICHAEL ANDREW FISCHBACH
• 金额: $ 46.74万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667586
• 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; Preleukemia; Process; Property; Proto-Oncogenes; Research; Resistance; Retroviridae; Role; Series; Shigella; Somatic Mutation; Spleen; Sterility; System; T cell response; Technology; Testing; Time; Tumor Escape; Tumor Promotion; 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.

抽象的 尽管某些逆转录病毒携带多种肿瘤，但逆转录病毒可在脊椎动物中诱发多种肿瘤。 由于其基因组中有致癌基因，绝大多数逆转录病毒不编码这些元件，因此，它们 诱导肿瘤的能力取决于细胞原癌基因附近的整合。 单独的激活不足以诱导肿瘤，肿瘤的发展需要额外的事件。 鼠白血病病毒 (MuLV) 可以通过口腔和血源性病原体传播，具有高度传染性。 有趣的是，同一品系的受感染小鼠的肿瘤发病率各不相同。 在不同研究实验室之间可能存在差异的环境因素中， 肠道微生物群的变化很突出。因此，我们试图确定微生物群是否有助于 因此，我们在无菌（GF，无菌）条件下监测了病毒诱导的白血病。 和无特定病原体（SPF）传统饲养 BALB/cJ 小鼠，即使 MuLV 复制和。 在没有微生物群的情况下，传播不会受到影响，GF 小鼠对微生物的抵抗力明显更强 与 SPF 小鼠相比，用一组确定的共生细菌（Altered Schaedler’s）定植 GF 小鼠的白血病率更高。 Flora），或单一细菌，例如鼠乳杆菌，但不是 Parabacteroides distasonis 或类似细菌 大肠杆菌和志贺氏菌 (SECS) 并没有改变病毒复制，但消除了其抗肿瘤表型 定植的小鼠，表明一些肠道微生物具有促进肿瘤的特性。 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，表明 肠道微生物通过抵消适应性免疫反应来促进白血病的发生。 白血病前脾脏的表达分析揭示了由 其中，“V-set 和 Ig 结构域 4”（VSig4）基因是已知的负调节因子。 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。 肠道微生物群与结肠癌和肝癌（“局部”）的进展有关 影响），以及通过增强抗癌免疫疗法的效果来发挥全身抗癌作用。 还有迹象表明微生物环境可以影响非病毒诱导的发育 为了确定肠道微生物群促进白血病的机制，我们将使用我们的方法。 病毒学、哺乳动物遗传学和生殖技术方面的专业知识（Golovkina 博士，芝加哥大学） 以及细菌遗传学和代谢组学方面的专业知识（Fischbach 博士，斯坦福大学）。 建议是：确定微生物调节的 VSig4 在病毒诱导的白血病发生中的作用； 表征导致病毒诱导白血病发展的细菌化合物； 肠道微生物群是否影响非病毒癌症模型中的白血病发展。

项目成果

Gut commensal bacteria enhance pathogenesis of a tumorigenic murine retrovirus.

• DOI: 10.1016/j.celrep.2022.111341
• 发表时间: 2022-09-13
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Spring, Jessica;Khan, Aly A.;Lara, Sophie;O'Grady, Kelly;Wilks, Jessica;Gurbuxani, Sandeep;Erickson, Steven;Fischbach, Michael;Jacobson, Amy;Chervonsky, Alexander;Golovkina, Tatyana
• 通讯作者: Golovkina, Tatyana