Deciphering the crosstalk between bacteria and their mammalian hosts

破译细菌与其哺乳动物宿主之间的串扰

• 批准号: 10473037
• 负责人: Aaron Thomas Whiteley
• 金额: $ 138.59万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473037
• 关键词: Alleles; Bacteria; Clinical; Development; Dinucleoside Phosphates; Effectiveness; Enzymes; Future; Generations; Health; Heterogeneity; Homologous Gene; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Individual; Language; Life; Malignant Neoplasms; Mammalian Cell; Mammals; Molecular; Pathway interactions; Periodicity; Play; Production; Role; Second Messenger Systems; Signal Transduction; Signaling Molecule; Stimulator of Interferon Genes; Therapeutic; Therapeutic Agents; Virus; anti-cancer; anti-cancer therapeutic; cancer immunotherapy; clinically relevant; commensal bacteria; gut bacteria; gut microbiome; human microbiota; microbiome; microbiota; pathogenic bacteria; patient response; receptor; small molecule

PROJECT SUMMARY The commensal bacteria that inhabit our microbiomes have a direct impact on human health. Recent studies have shown that bacteria in the gut can even alter patient responsiveness to immune checkpoint inhibitors, the latest generation of anticancer immunotherapy. The mechanisms of how bacteria influence the immune response to cancer are poorly understood; therefore, understanding bacterium-human interactions at the molecular level is critical to our understanding of the immune system, disease, and therapeutics. An important way that bacteria influence human cell signaling is through the production of small molecules that activate or inhibit human cellular receptors. We are specifically focused on how diverse bacteria manipulate the mammalian cGAS-STING pathway, a clinically relevant pathway that is critical for the immune response to cancer, as well as viruses and pathogenic bacteria. In humans, cGAS generates a cyclic dinucleotide second messenger that activates STING, which is the crucial step for initiating anticancer signaling. We recently made the unexpected finding that bacteria of the gut microbiome encode enzymes homologous to cGAS. Bacterial cGAS synthesizes cyclic dinucleotides that agonize STING, and cyclic dinucleotides released by bacteria can be taken up by mammalian cells. Cyclic dinucleotides thus provide a molecular basis for bacteria to manipulate the human cGAS-STING pathway and offer a shared molecular language for crosstalk between the microbiota and mammalian cells. Although bacterial and mammalian cGAS are highly similar, there are important differences in the heterogeneity of their cyclic dinucleotide products and studying these differences will decipher the crosstalk between these domains of life. Mammals synthesize one potent second messenger while bacterial cGAS-like enzymes are highly diverse. Different bacteria produce unique cyclic dinucleotide products that vary in their ability to agonize STING and additional human immune pathways. This proposal investigates the hypothesis that bacteria in the microbiome expressing different bacterial cGAS alleles can alter host STING signaling, the host immune response to cancer, and the effectiveness of cancer immunotherapy. First, we will investigate the role of specific bacteria expressing cGAS homologues in altering effectiveness of cancer immunotherapy. Next, we will interrogate known bacterial strains that alter patient responsiveness to cancer immunotherapy for production of cyclic dinucleotides. Finally, we will explore the human immune pathways, including STING, that are activated by the full range of diverse cyclic dinucleotides synthesized by bacteria. This proposal is focused on the mechanisms by which bacteria alter patient responsiveness to cancer immunotherapy; however, I expect results from these studies to be broadly relevant to our understanding how specific bacteria in the human microbiota influence human health and will advance the clinical utility of cyclic dinucleotides as therapeutic agents.

项目摘要 栖息在我们微生物群中的肠道细菌对人类健康有直接影响。最近的研究 已经表明肠道中的细菌甚至可以改变患者对免疫检查点抑制剂的反应， 最新一代的抗癌免疫疗法细菌如何影响免疫的机制 对癌症的反应知之甚少;因此，了解细菌与人类的相互作用， 分子水平对我们理解免疫系统、疾病和治疗方法至关重要。一个重要 细菌影响人类细胞信号传导的方式是通过产生小分子， 抑制人类细胞受体。我们特别关注不同的细菌如何操纵 哺乳动物cGAS-STING途径，一种临床相关的途径，对于免疫应答至关重要， 癌症以及病毒和致病细菌。在人类中，cGAS产生环状二核苷酸第二个 STING是启动抗癌信号传导的关键步骤。我们最近 肠道微生物组的细菌编码与cGAS同源的酶的意外发现。细菌 cGAS合成激动STING的环状二核苷酸，并且由细菌释放的环状二核苷酸可以 被哺乳动物细胞吸收。因此，环状二核苷酸为细菌操纵 人类cGAS-STING通路，并为微生物群之间的串扰提供共享的分子语言 和哺乳动物细胞。虽然细菌和哺乳动物的cGAS高度相似，但重要的是， 它们的环状二核苷酸产物的异质性的差异，研究这些差异将 破译这些生命领域之间的相互联系。哺乳动物合成一种有效的第二信使 而细菌cGAS样酶是高度多样的。不同的细菌产生独特的环状二核苷酸 这些产品激动STING和其他人类免疫途径的能力不同。这项建议 研究了微生物组中表达不同细菌cGAS等位基因的细菌可以 改变宿主STING信号传导，宿主对癌症的免疫反应，以及癌症的有效性 免疫疗法。首先，我们将研究表达cGAS同源物的特定细菌在改变 癌症免疫治疗的有效性。接下来，我们将询问已知的细菌菌株， 用于产生环状二核苷酸的对癌症免疫疗法的响应性。最后，我们将探讨 人类免疫途径，包括STING，由各种不同的环状二核苷酸激活 是由细菌合成的这项提案的重点是细菌改变病人的机制。 对癌症免疫治疗的反应;但是，我预计这些研究的结果具有广泛的相关性 我们了解人类微生物群中的特定细菌如何影响人类健康， 环状二核苷酸作为治疗剂的临床应用。