Protection from enteric pathogens by beneficial microbes

通过有益微生物预防肠道病原体

• 批准号: 8546976
• 负责人: Katherine L. Knight
• 金额: $ 14.19万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546976
• 关键词: Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacillus (bacterium); Bacillus licheniformis; Bacillus subtilis; Bacteria; C-Type Lectins; CD4 Positive T Lymphocytes; Cells; Child; Citrobacter rodentium; Disease; Dose; Escherichia coli EHEC; Exposure to; Flagellin; Flow Cytometry; Gastrointestinal tract structure; Goals; Grant; Homeostasis; Immune; Immune response; Inflammation; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Knock-out; Knockout Mice; Ligands; Luciferases; Mediating; Mesentery; Microbe; Mus; Natural Immunity; Oral; Peptidoglycan; RIPK2 gene; Receptor Signaling; Regulatory T-Lymphocyte; Reproduction spores; Site; TLR2 gene; TLR5 gene; Testing; Toll-like receptors; bioluminescence imaging; commensal microbes; design; enteric pathogen; in vivo; intestinal epithelium; killings; lymph nodes; mutant; pathogen; prevent; receptor; research study

DESCRIPTION (provided by applicant): The host and its commensal microbiota generally maintain a peaceful coexistence; however, a few bacteria disrupt immune homeostasis and cause disease. For example, attaching and effacing (A/E) enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) cause diarrheal diseases that affect more than 2 billion people and kill 1.5 million children annually. Commensal bacteria can protect the host from disease caused by enteric pathogens; however, the mechanisms by which this occurs are poorly understood. We recently found that a single oral dose of commensal Bacillus subtilis or Bacillus formis spores can protect mice from disease caused by the A/E pathogen, Citrobacter rodentium. In contrast, a closely related commensal Bacillus licheniformis, and two B. subtilis mutants, hag and espH, did not protect the host. Because the single dose of protective Bacillus spp. is given 24 hr prior to pathogenic C. rodentium, protection is not likely due to initiation of an adaptive immune response, but is more likely due to an innate anti-inflammatory immune response. Alternatively, Bacillus spp. could protect from disease by directly interfering with localization of C. rodentium to the intestinal epithelium. In Aim 1 we will use in vivo bioluminescence imaging (IBIS) to determine if protective Bacillus spp. alter the colonization site of pathogenic C. rodentium. One of the non-protective B. subtilis mutants is deficient in flagellin, a ligand for TLR5, and another is deficient in exopolysaccharide, presumed ligand for TLR2, and in Aim 2 we will use TLR agonists and TLR knockout mice to determine if protection is mediated through TLR. Similarly, we will use Nod-like receptor (NLR) agonists and knockout mice to determine if protection is mediated through NLR. In Aim 3, we will test the possibility that B. subtilis mediates protection through T regulatory cells.

描述（由申请人提供）：宿主及其肠道微生物群通常保持和平共处;然而，少数细菌破坏免疫稳态并引起疾病。例如，附着和消除（A/E）肠致病性和肠出血性E。大肠杆菌（EPEC和EHEC）引起的肠道疾病每年影响超过20亿人，并导致150万儿童死亡。共生细菌可以保护宿主免受肠道病原体引起的疾病的侵害;然而，这种情况发生的机制知之甚少。我们最近发现，单次口服剂量的枯草芽孢杆菌或芽孢杆菌孢子可以保护小鼠免受由A/E病原体啮齿柠檬酸杆菌引起的疾病。与此相反，一个密切相关的地衣芽孢杆菌，和两个B。枯草杆菌突变体hag和espH不能保护宿主。因为单剂量的保护性芽孢杆菌。在致病性C之前24小时给予。在啮齿动物中，保护不太可能是由于适应性免疫应答的启动，而更可能是由于先天性抗炎免疫应答。或者，芽孢杆菌属（Bacillus spp.）可以通过直接干扰C.啮齿动物的肠上皮细胞。在目标1中，我们将使用体内生物发光成像（IBIS）来确定是否保护芽孢杆菌属。改变致病性C.啮齿动物。其中一个非保护性的B。枯草芽孢杆菌突变体缺乏鞭毛蛋白（TLR 5的配体），另一种缺乏胞外多糖（推测为TLR 2的配体），在目的2中，我们将使用TLR激动剂和TLR敲除小鼠来确定保护是否通过TLR介导。同样，我们将使用Nod样受体（NLR）激动剂和基因敲除小鼠来确定保护是否是通过NLR介导的。在目标3中，我们将测试B.枯草芽孢杆菌通过调节性T细胞介导保护作用。