Programming innate immune responses using glycomimetic macromolecular complexes

使用拟糖大分子复合物编程先天免疫反应

• 批准号: 1808459
• 负责人: Gerard Wong
• 金额: $ 63.93万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808459&HistoricalAwards=false
• 关键词: Programming; innate; immune; responses; using

Non-Technical abstract: Innate immunity is a part of the immune system that recognizes specific chemical patterns used in pathogens (ex: bacteria, viruses, and fungi) but not common to our cells and mammalian cells. These patterns include double-stranded RNA, certain types of DNA and sugar-based molecules known as lipopolysaccharides (LPS). Detection of these molecular patterns is a potential sign of invasion, and trigger defensive responses. It has been discovered that certain molecules that are not supposed to be detected by the innate immune system can in fact stimulate and greatly amplify this innate immune response, by simply forming organized structures with DNA and with RNA. This is completely unexpected, and can potentially revise fundamental understanding of molecular recognition. The goal of this proposed research is to understand the rules governing these phenomena, and design and test new synthetic molecules that can mimic this immune system amplification, and to design new synthetic molecules that can turn off this process. The basic knowledge gained as a result of this research will be broadly enabling. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. This work will broaden participation in a number of ways. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes. Technical abstract:Innate immunity is a non-specific defense mechanism against pathogens bearing specific chemical recognition motifs not common to mammalian cells. Detection of these pathogen-associated molecular patterns (PAMPs) signals the presence of foreign cells, and trigger inflammatory responses. Toll-like receptors (TLRs) are capable of recognizing specific immune ligand classes: dsRNA is recognized by TLR3, while TLR9 recognizes pathogenic dsDNA; both activate signal transduction pathways that lead to the production of pro-inflammatory cytokines and upregulation of antimicrobial peptides (AMPs) for pathogen defense. Recent work from his research group on TLR9 and TLR3 activation reveal a new, unexpected physical basis for immunomodulation. Molecules with specific structural characteristics can co-assemble with immune ligands into nanocrystalline complexes that drastically upregulate immune responses: The spatially-periodic presentation of immune ligands by these complexes drive amplification via intercalative binding with multiple TLRs. This represents a significant generalization of the central paradigm in molecular recognition. Innate immune receptors can recognize not just PAMPs on single ligand molecules, but also recognize nanocrystalline arrangements of ligands. Here, the aim is to understand this new type of molecular recognition, and design chemically-cognate, structurally-characterized families of self-assembled dsDNA complexes and quantitatively control downstream immune stimulation. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes.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.

非技术摘要：先天免疫是免疫系统的一部分，它识别病原体（例如：细菌，病毒和真菌）中使用的特定化学模式，但对我们的细胞和哺乳动物细胞来说并不常见。这些模式包括双链RNA，某些类型的DNA和称为脂多糖（LPS）的糖基分子。 检测到这些分子模式是入侵的潜在信号，并触发防御反应。已经发现，某些不应该被先天免疫系统检测到的分子实际上可以通过简单地与DNA和RNA形成有组织的结构来刺激并极大地放大这种先天免疫应答。这是完全出乎意料的，可能会改变对分子识别的基本理解。这项拟议研究的目标是了解这些现象的规则，设计和测试可以模拟这种免疫系统扩增的新合成分子，并设计可以关闭这一过程的新合成分子。 从这项研究中获得的基本知识将广泛发挥作用。潜在的长期结果包括更好地控制免疫系统的生物材料和更好的检测特定化学物质的传感器。这项工作将以多种方式扩大参与。拟议工作的多学科性质将在这一新兴领域提供充分的教育机会。这里的研究课题有利于学术和工业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展计划提供。由此产生的结果将被纳入PI的高级本科/研究生课程。技术摘要：先天免疫是一种针对病原体的非特异性防御机制，其具有哺乳动物细胞不常见的特异性化学识别基序。这些病原体相关分子模式（PAMP）的检测表明外源细胞的存在，并引发炎症反应。Toll样受体（TLR）能够识别特定的免疫配体类别：dsRNA被TLR 3识别，而TLR 9识别致病性dsDNA;两者都激活信号转导途径，导致促炎细胞因子的产生和抗菌肽（AMP）的上调，用于病原体防御。他的研究小组最近对TLR 9和TLR 3激活的研究揭示了免疫调节的一个新的、意想不到的物理基础。具有特定结构特征的分子可以与免疫配体共组装成纳米晶复合物，其显著上调免疫应答：这些复合物对免疫配体的空间周期性呈递通过与多个TLR的嵌入结合驱动扩增。这代表了分子识别中中心范式的重要推广。先天性免疫受体不仅可以识别单个配体分子上的PAMP，还可以识别纳米晶排列的配体。在这里，目的是了解这种新型的分子识别，并设计自组装dsDNA复合物的化学同源，结构特征的家族，并定量控制下游免疫刺激。潜在的长期结果包括更好地控制免疫系统的生物材料和更好的检测特定化学物质的传感器。拟议工作的多学科性质将在这一新兴领域提供充分的教育机会。这里的研究课题有利于学术和工业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展计划提供。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

• DOI: 10.1021/acsinfecdis.0c00011
• 发表时间: 2020-05-08
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Dishman, Acacia F.;Lee, Michelle W.;Volkman, Brian F.
• 通讯作者: Volkman, Brian F.

PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

• DOI: 10.1073/pnas.1917623117
• 发表时间: 2021-01-05
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Lee, Ernest Y.;Chan, Liana C.;Wong, Gerard C. L.
• 通讯作者: Wong, Gerard C. L.

How do cyclic antibiotics with activity against Gram-negative bacteria permeate membranes? A machine learning informed experimental study.

• DOI: 10.1016/j.bbamem.2020.183302
• 发表时间: 2020-08-01
• 期刊: Biochimica et biophysica acta. Biomembranes
• 作者: Lee MW;de Anda J;Kroll C;Bieniossek C;Bradley K;Amrein KE;Wong GCL
• 通讯作者: Wong GCL

Assembly of ordered DNA-curli fibril complexes during Salmonella biofilm formation correlates with strengths of the type I interferon and autoimmune responses.

• DOI: 10.1371/journal.ppat.1010742
• 发表时间: 2022-08
• 期刊: PLoS pathogens
• 影响因子: 6.7

Discovery of Novel Type II Bacteriocins Using a New High-Dimensional Bioinformatic Algorithm

• DOI: 10.3389/fimmu.2020.01873
• 发表时间: 2020-09
• 期刊: Frontiers in Immunology
• 影响因子: 7.3
• 作者: N. Yount;D. C. Weaver;J. de Anda;Ernest Y Lee;Michelle W. Lee;G. Wong;M. Yeaman