Exploiting the Salivary Arsenal to Inhibit Diarrheal Disease

利用唾液库抑制腹泻病

• 批准号: 10357830
• 负责人: ESTHER BULLITT
• 金额: $ 20.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357830
• 关键词: Adherence; Adhesives; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Adhesion; Bacterial Infections; Binding; Biological Models; Cell Culture Techniques; Cell Wall; Cells; Cessation of life; Child; Cryoelectron Microscopy; Data; Development; Diarrhea; Disease; Drug Design; Effectiveness; Enterobacteriaceae; Enzymes; Filament; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Health; Human; Immune; Innate Immune System; Intestines; Natural Immunity; Nucleic Acids; Organoids; Oropharyngeal; Outcomes Research; Pathogenicity; Peptides; Periodontal Diseases; Pilum; Property; Proteins; Proteome; Research; Research Personnel; Resolution; Respiratory Disease; Role; Route; Saliva; Salivary; Structure; Surface; Testing; Therapeutic; Therapeutic Agents; Virulence Factors; Vulnerable Populations; antimicrobial; antimicrobial peptide; base; combat; design; diarrheal disease; efficacy testing; enterotoxigenic Escherichia coli; fighting; histatin 5; inhibitor; innovation; novel; novel strategies; novel therapeutic intervention; oral infection; oral pathogen; pathogen; peptide drug; prevent; prophylactic; respiratory; respiratory pathogen; therapeutic development

The ability of salivary peptides to inhibit diarrhea-causing bacteria from binding to the gut is newly discovered, and not well characterized. The innovative long-term goal is to realize the full potential of salivary components as both prophylactic and therapeutic agents against gastrointestinal and respiratory diseases. The objectives of this proposal are to define the efficacy of specific salivary components as pathogen inhibitors, and to determine the structure and mechanism by which one these peptides, Histatin-5, binds to pili that are external filaments on enterotoxigenic Escherichia coli (ETEC). This pilus/peptide interaction provides the dysfunction that inhibits bacterial binding, and knowing the mechanism of this dysfunction will lead to novel therapeutic approaches against ETEC and other pathogens. The central hypothesis is that enhanced utilization of the innate immune system to combat disease can be achieved through therapeutics developed from components of saliva. The rationale for this proposal is that completion of this research provides a path forward for utilizing salivary components to fight diarrheal diseases. In addition, determination of the mechanism of Histatin-5's action will permit creation of therapeutics with even greater efficacy. To achieve our goals, we will pursue the following two specific aims: 1. Define the capacity of selected salivary peptides to inhibit bacterial binding of enterotoxigenic Escherichia coli (ETEC) to target cells; 2. Determine the mechanism by which the salivary peptide, Histatin-5, inhibits bacterial binding via pili, an essential virulence factor of enterotoxigenic Escherichia coli (ETEC). These aims will be achieved using 1) bacterial adhesion studies on cell cultures and primary human intestinal cultures (“organoids”) and 2) structure determination at high resolution using electron cryomicroscopy and cryotomography (cryo-EM and cryo-ET). The proposed research is significant, because it will open a new avenue for development of therapeutics against diarrhea-causing bacteria. Unlike traditional antibiotics that broadly target enzymes involved in nucleic acid, protein, and cell wall synthesis, here, we explore a novel aspect of the host's innate immune system: the ability of salivary components to inhibit bacterial adherence to the host. The expected outcome of this research is a list of salivary components that can be exploited as therapeutics against diarrhea-causing pathogens, and the definition of the mechanism by which one component creates dysfunction of a critical virulence factor. The results will have an important positive impact immediately as a first step in defining and understanding the role of saliva in fighting GI disease, and long-term because they will lay the groundwork for bringing new researchers into this emerging field, and for development of saliva-based GI and respiratory therapeutics.

唾液肽抑制腹泻的细菌与肠道结合的能力是新的 发现，没有很好的特征。创新的长期目标是实现唾液的全部潜力 针对胃肠道和呼吸系统疾病的预防剂和治疗剂的成分。这 该提案的目标是将特定唾液成分的有效性定义为病原体抑制剂，并且 确定这些肽Histatin-5与PILI结合的结构和机制 肠毒素大肠杆菌（ETEC）上的外丝。这种飞行员/肽相互作用提供了 抑制细菌结合的功能障碍，并且知道这种功能障碍的机制将导致新颖 针对ETEC和其他病原体的治疗方法。中心假设是增强的利用率 可以通过从 唾液的成分。该提议的理由是，这项研究的完成为前进提供了途径 用于利用唾液成分来抵抗腹泻疾病。另外，确定机制 Histatin-5的动作将允许以更高的效率创建治疗剂。为了实现我们的目标，我们将 追求以下两个具体目标： 1。定义选定的唾液辣椒抑制肠毒素的细菌结合的能力 大肠杆菌（ETEC）到靶细胞； 2。确定唾液肽Histatin-5通过pili抑制细菌结合的机制 肠毒素大肠杆菌（ETEC）的必需病毒因子。 这些目标将使用1）细菌粘附研究和原代人的细菌粘附研究 肠道培养物（“器官”）和2）使用电子设备高分辨率下的结构测定 冷冻显微镜和冷冻学（Cryo-EM和Cryo-ET）。拟议的研究很重要，因为它 将为针对引起腹泻的细菌开发疗法的新途径。与传统不同 广泛靶向参与核酸，蛋白质和细胞壁合成的酶，在这里，我们 探索宿主先天免疫系统的新颖方面：唾液成分抑制的能力 细菌遵守宿主。这项研究的预期结果是唾液成分清单 可以探讨作为针对腹泻病原体的治疗，以及该机制的定义 哪一个成分会导致关键病毒因子的功能障碍。结果将具有重要的 立即将积极影响作为定义和理解唾液在与GI作斗争中的作用的第一步 疾病，长期是因为它们将为将新研究人员带入这一新兴 领域，以及开发基于唾液的GI和呼吸疗法。

项目成果

New Morphologies of Hib Adhesion Pili.

Hib 粘附菌毛的新形态。

• DOI: 10.1093/micmic/ozad067.466
• 发表时间: 2023
• 期刊: Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada
• 作者: Thairatana,Siriratt;Doran,Matthew;Sonani,RaviR;Egelman,EdwardH;Bullitt,Esther
• 通讯作者: Bullitt,Esther

Unveiling molecular interactions that stabilize bacterial adhesion pili.

• DOI: 10.1016/j.bpj.2022.04.036
• 发表时间: 2022-06-07
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Dahlberg, Tobias;Baker, Joseph L.;Bullitt, Esther;Andersson, Magnus
• 通讯作者: Andersson, Magnus

Three structural solutions for bacterial adhesion pilus stability and superelasticity.

• DOI: 10.1016/j.str.2023.03.005
• 发表时间: 2023-05-04
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Doran, Matthew H.;Baker, Joseph L.;Dahlberg, Tobias;Andersson, Magnus;Bullitt, Esther
• 通讯作者: Bullitt, Esther

Gut check: can other microbes or communities phenocopy H. pylori's early gastric pathology?

• DOI: 10.1136/gutjnl-2021-325749
• 发表时间: 2022-07
• 期刊: Gut
• 影响因子: 24.5
• 作者: Brown JW