CAREER: Uncovering natural metabolite influences on anti-bacteriophage defenses

职业：揭示天然代谢物对抗噬菌体防御的影响

• 批准号: 2143636
• 负责人: Joseph Gerdt
• 金额: $ 125.93万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143636&HistoricalAwards=false
• 关键词: CAREER; Uncovering; natural; metabolite; influences

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Bacteria can get “sick” too; they can be infected by bacteriophage viruses (or “phages”). The world needs to care about the health of bacteria because many bacteria help humans (food production, medicine production, probiotics), and some bacteria hurt humans (infect humans, destroy food, contaminate industrial processes). Therefore, viruses that infect beneficial bacteria can be problematic, but viruses that infect harmful bacteria actually can help humans. The proposed research program will uncover conditions that help bacteria evade infections by phages. The findings will reveal approaches to protect beneficial bacteria and to leverage viruses to kill harmful bacteria. The research team will be composed of undergraduate students and graduate students from diverse backgrounds, as well as individuals with intellectual and developmental disabilities. This team with diverse backgrounds and abilities will collaborate in genuine scientific discovery. The success of this unique team will be evaluated, and the lessons learned will be distributed to the broader scientific community to help others assemble similar STEM teams.Bacteria have evolved myriad immune systems to protect themselves from viruses (bacteriophages). However, it is unclear how these immune defenses are influenced by local environments. For example, bacteria frequently are found in polymicrobial communities. While there, bacteria are bombarded by a metabolites secreted by their neighbors. These metabolites are likely to influence the efficacy of the antiviral immune systems of the bacteria. Therefore, it is unclear how significant anti-phage defenses are at providing immunity within complex microbiomes. The proposed work will advance knowledge to fill this gap. Specifically, the research team will 1) identify the specific pure metabolites that modulate each of five different antiviral defenses, 2) elucidate the mechanisms by which the metabolites elicit their effects, and 3) determine the prevalence of these metabolite/immunity interactions in host-associated and environmental niches. By characterizing metabolites that modulate antiviral defenses, this research will define specific biochemical environments in which anti-phage defenses provide altered immunity. The community can then leverage metagenomic data to determine the likelihood of the anti-phage defenses to co-occur with these metabolites that modulate them. Furthermore, many antiviral immune systems are incompletely understood. By uncovering the mechanisms of action of the first chemical modulators of these defenses, this project will reveal new details about how these defenses confer immunity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。细菌也可能“生病”；它们可能被噬菌体病毒(或称“噬菌体”)感染。世界需要关心细菌的健康，因为许多细菌帮助人类(食品生产、药品生产、益生菌)，而一些细菌伤害人类(感染人类、破坏食品、污染工业流程)。因此，感染有益细菌的病毒可能会有问题，但感染有害细菌的病毒实际上可以帮助人类。拟议的研究计划将揭示帮助细菌逃避噬菌体感染的条件。这些发现将揭示保护有益细菌和利用病毒杀死有害细菌的方法。研究团队将由来自不同背景的本科生和研究生以及智力和发育障碍的个人组成。这个拥有不同背景和能力的团队将在真正的科学发现方面进行合作。这个独特的团队的成功将得到评估，所学到的经验将被分发给更广泛的科学界，以帮助其他人组建类似的STEM团队。细菌已经进化出无数的免疫系统来保护自己免受病毒(噬菌体)的攻击。然而，目前还不清楚这些免疫防御是如何受到当地环境的影响的。例如，细菌经常在多菌群中被发现。在那里，细菌受到邻居分泌的代谢物的轰炸。这些代谢物可能会影响细菌的抗病毒免疫系统的疗效。因此，目前尚不清楚抗噬菌体防御在复杂微生物群中提供免疫的重要性。拟议的工作将促进填补这一空白的知识。具体地说，研究小组将1)确定调节五种不同抗病毒防御的特定纯代谢物，2)阐明代谢物引起其影响的机制，以及3)确定这些代谢物/免疫相互作用在宿主相关和环境利基中的流行程度。通过表征调节抗病毒防御的代谢物，这项研究将定义特定的生化环境，在这种环境中，抗噬菌体防御提供改变的免疫。然后，该社区可以利用元基因组数据来确定抗噬菌体防御与调节它们的代谢物共同出现的可能性。此外，许多抗病毒免疫系统还不完全了解。通过揭示这些防御的第一批化学调节剂的作用机制，该项目将揭示这些防御如何授予豁免权的新细节。这一裁决反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。