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

免疫系统是动物对抗病原微生物的主要方式之一。动物还与数百万非致病微生物(它们的微生物群)生活在一起，这些微生物不会对它们造成伤害。越来越多的证据表明，免疫系统与这些微生物群建立了密切的关系，这可能会决定暴露在病原体下的动物的生死。两栖动物说明了研究微生物群、免疫系统和病原体之间相互作用的重要性。全球各地的两栖动物都死于壶菌巴氏杆菌(Bd)感染。BD会感染两栖动物的皮肤，并通过破坏基本的皮肤功能而导致死亡。两栖类皮肤微生物组和免疫系统成分已被证明与Bd感染结果独立相关。然而，宿主微生物群、宿主免疫系统和病原体Bd之间的相互作用仍然知之甚少。这种微生物-免疫界面可能是决定Bd感染结果的关键。这项拟议的研究是独特和创新的，因为研究人员将使用三种不同的两栖动物物种进行实验室实验，这些物种对Bd的易感性不同，并采用最先进的分子和分析方法。在这项由史密森学会、乔治华盛顿大学、乔治梅森大学(美国)和班戈大学(英国)的研究人员合作的项目中，研究人员旨在确定控制微生物-免疫界面的机制及其对Bd易感性的影响。他们希望证明两栖动物皮肤微生物群和宿主免疫反应是相互联系的、多方面的系统，而不是离散的宿主和微生物实体。指导这项研究的中心假设是，两栖动物皮肤微生物群和常驻免疫细胞群之间的相互依赖关系关键地决定了Bd感染的结果。这个跨学科的研究团队将在多个实验规模上整合微生物生态学、比较免疫学、转录组学和蛋白质组学。他们将把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，以检查两栖动物皮肤微生物-免疫界面及其对两栖动物对Bd感染引起的旋毛菌病易感性的影响。他们将通过以下方式解决他们的假设：1)确定皮肤微生物如何影响皮肤免疫细胞群，2)定义皮肤常驻免疫细胞如何影响皮肤微生物群，3)解决微生物-免疫界面在BD感染结果中的贡献。他们预测，关键的微生物-免疫相互作用强烈影响Bd的易感性。他们的发现将获得对微生物-免疫界面以及这些相互作用如何影响疾病结果的迫切需要的理解。他们的研究将是第一次在因果框架内同时评估微生物组和免疫系统对棘球菌病的相对贡献。包括人类在内的脊椎动物是共生微生物和复杂免疫系统组件的宿主。从这些研究中得到的洞察力将广泛适用于各种其他动物系统。这一美英合作项目得到了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。这一奖项反映了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。

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.