Collaborative Research: NSF-BIO/BBSRC: The amphibian skin microbial-immune interface and its impact on infection outcome

合作研究：NSF-BIO/BBSRC：两栖动物皮肤微生物免疫界面及其对感染结果的影响

• 批准号: 2131061
• 负责人: Leon Grayfer
• 金额: $ 27.6万
• 依托单位: George Washington University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2131061&HistoricalAwards=false
• 关键词: Collaborative; Research; NSF; BIO; BBSRC

The immune system is one of the primary ways animals fight pathogenic microorganisms. Animals also live with millions of non-pathogenic microorganisms (their microbiomes) which cause them no harm. Accumulating evidence indicates that immune systems establish intimate relationships with these microbiomes, which may make the difference between life and death for an animal exposed to a pathogen. Amphibians exemplify the importance of studying interactions among microbiomes, immune systems and pathogens. Amphibians across the globe are dying from infection by the chytrid fungus Batrachochytrium dendrobatidis (Bd). Bd infects the skin of amphibians and causes death by disruption of essential skin function. Amphibian skin microbiome and immune system components have been shown to independently relate to Bd infection outcomes. Yet, the interactions among host microbiomes, host immune systems and the pathogen Bd remain poorly understood. This microbial-immune interface is likely critical to determining Bd infection outcomes. The proposed research is unique and innovative because the investigators will combine laboratory experiments using three amphibian species that differ in Bd susceptibility with state-of-the-art molecular and analytical approaches. In this project, which is a collaboration between researchers at the Smithsonian Institution, George Washington University and George Mason University (US) and Bangor University (UK), the investigators aim to define the mechanisms controlling the microbial-immune interface and its effect on Bd susceptibility. They expect to demonstrate that amphibian skin microbiomes and host immune responses are interconnected, multi-facetted systems rather than discrete host and microbial entities. The central hypothesis guiding the proposed studies is that the interdependence of amphibian skin microbiomes and resident immune cell populations critically define Bd infection outcomes. The interdisciplinary research team will integrate microbial ecology, comparative immunology, meta-transcriptomics and proteomics at multiple experimental scales. They will combine these comprehensive system-level datasets with network analyses and structural equation modeling to examine the amphibian skin microbial-immune interface and its effect on amphibian susceptibility to the disease chytridiomycosis, caused by Bd infection. They will address their hypothesis by: 1) determining how skin microbiomes affect skin immune cell populations, 2) defining how skin-resident immune cells affect skin microbiomes, 3) resolving the contribution of the microbial-immune interface in Bd infection outcomes. They predict that key microbial-immune interactions strongly impact Bd susceptibility. Their findings will garner the much-needed understanding of the microbial-immune interface and how these interactions impact disease outcomes. Theirs will be the first study to simultaneously evaluate the relative contribution of the microbiome and immune system to chytridiomycosis in a causal framework. Vertebrate animals, including humans, are host to symbiotic microbes and complex immune system components. The resulting insight from these investigations will have broad applicability to a variety of other animal systems. This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.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.

免疫系统是动物抗击致病微生物的主要方式之一。动物还生活在数百万个非致病微生物（其微生物组）中，这不会造成它们的伤害。积累的证据表明，免疫系统与这些微生物组建立了密切的关系，这可能会使暴露于病原体的动物生与死之间有所不同。两栖动物体现了研究微生物，免疫系统和病原体之间相互作用的重要性。全球两栖动物因chytrid真菌batrachochytrium dendrobatidis（BD）而死于感染。 BD感染两栖动物的皮肤，并通过破坏必需皮肤功能而导致死亡。两栖动物皮肤微生物组和免疫系统成分已显示与BD感染结果独立相关。然而，宿主微生物组，宿主免疫系统和病原体BD之间的相互作用仍然很少了解。这种微生物免疫接口可能对于确定BD感染结果至关重要。拟议的研究具有独特性和创新性，因为研究人员将使用三种两栖动物将实验室实验结合在一起，这些两栖动物在BD易感性上与最先进的分子和分析方法不同。在这个项目中，这是史密森尼机构，乔治华盛顿大学和乔治·梅森大学（美国）和班戈大学（英国）研究人员之间的合作，研究人员旨在定义控制微生物 - 免疫接口的机制及其对BD易感性的影响。他们希望证明两栖动物皮肤微生物组和宿主免疫反应是相互联系的，多面的系统，而不是离散的宿主和微生物实体。 指导拟议研究的中心假设是两栖动物皮肤微生物组和驻留的免疫细胞种群的相互依存关系严重定义了BD感染结果。跨学科研究团队将在多个实验量表上整合微生物生态学，比较免疫学，荟萃分解组和蛋白质组学。他们将将这些全面的系统级数据集与网络分析和结构方程建模相结合，以检查两栖动物的皮肤微生物 - 免疫接口及其对由BD感染引起的对两栖动物对疾病循环菌病的影响。他们将通过以下方法来解决其假设：1）确定皮肤微生物如何影响皮肤免疫细胞群体，2）定义皮肤居住的免疫细胞如何影响皮肤微生物组，3）解决BD感染成果中微生物 - 免疫界面的贡献。他们预测，关键的微生物 - 免疫相互作用会严重影响BD易感性。他们的发现将获得对微生物免疫接口的急需的理解，以及这些相互作用如何影响疾病结果。它们将是第一个同时评估微生物组和免疫系统在因果框架中造乳菌病的相对贡献的研究。包括人在内的脊椎动物是共生微生物和复杂的免疫系统成分的宿主。这些调查中产生的见解将对其他各种动物系统具有广泛的适用性。美国国家科学基金会和英国生物技术和生物科学研究委员会的支持。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估审查标准的评估来支持的。

项目成果

A comparison of amphibian (Xenopus laevis) tadpole and adult frog macrophages

两栖动物（非洲爪蟾）蝌蚪和成年青蛙巨噬细胞的比较

• DOI: 10.1016/j.dci.2023.104647
• 发表时间: 2023
• 期刊: Developmental & Comparative Immunology
• 影响因子: 2.9
• 作者: Hossainey, Muhammad Riadul;Yaparla, Amulya;Uzzaman, Zarafsha;Moore, Tyler;Grayfer, Leon
• 通讯作者: Grayfer, Leon

One Health Approach to Globalizing, Accelerating, and Focusing Amphibian and Reptile Disease Research-Reflections and Opinions from the First Global Amphibian and Reptile Disease Conference.

• DOI: 10.3201/eid2910.221899
• 发表时间: 2023-10
• 期刊: Emerging infectious diseases
• 影响因子: 11.8
• 作者: Gray MJ;Ossiboff RJ;Berger L;Bletz MC;Carter ED;DeMarchi JA;Grayfer L;Lesbarrères D;Malagon DA;Martel A;Miller DL;Pasmans F;Skerratt LF;Towe AE;Wilber MQ
• 通讯作者: Wilber MQ