Genetic Determinants of Mucosal Defense to Salmonella Infection

沙门氏菌感染粘膜防御的遗传决定因素

• 批准号: 7898725
• 负责人: Kelly D Smith
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898725
• 关键词: A/J Mouse; Acute; B-Lymphocytes; Bacteria; Bacterial Infections; Biological Assay; Biological Models; C57BL/6 Mouse; Candidate Disease Gene; Cecum; Cells; Chromosomes; Chromosomes, Human, Pair 1; Chronic; Colon; Complex; Consomic Strain; Coupled; Cytokine Receptors; Defect; Defense Mechanisms; Detection; Disease; Dose; Environmental Risk Factor; Epithelium; Evolution; Face; Failure; Food Contamination; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Determinism; Genetic Variation; Goals; Granulomatous; Hand; Health; Histologic; Histology; Human; Immune; Immune response; Immune system; Immunity; Immunologic Factors; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Mucosa; Knowledge; Large Intestine; Lead; Liver; Mesentery; Microbe; Modeling; Molecular; Molecular Genetics; Mucosal Immunity; Mucositis; Mus; Natural regeneration; Oral; Organism; Outcome; Pathology; Pathway interactions; Phase; Phenotype; Process; Route; Salmonella; Salmonella infections; Salmonella typhi; Salmonella typhimurium; Self Tolerance; Site; Small Intestines; Spleen; Surface; Systemic infection; Testing; Time; Typhoid Fever; Ulcer; United States; Vaccine Design; Virus; commensal microbes; consomic; cytokine; defined contribution; improved; insight; lymph nodes; mouse model; mucosal vaccine; novel; oral infection; pathogen; pathogenic bacteria; prevent; response; therapeutic vaccine; transmission process

DESCRIPTION (provided by applicant): The mucosal immune system must simultaneously decipher pathogens from innocuous flora and maintain self tolerance while promoting long-lasting immunity to pathogens. In the gut, and especially the large intestine, this is a considerable task, where the commensal microbes comprise approximately 1012 cells per gram contents. We have characterized oral infection by Salmonella in C57BL/6, A/J and 129S1 mice, and demonstrated that this infection progresses toward 3 distinct outcomes. C57BL/6 mice gradually develop cecal infection but are rapidly overwhelmed by systemic infection. A/J mice develop rapid colonization of the cecum followed by chronic persistent infection and inflammation. 129S1 mice gradually develop cecal infection and inflammation, and proceed to resolve the infection and inflammation. We hypothesize that host genetic differences are major determinants of these divergent outcomes. In this proposal, we will use a two pronged approach to decipher important functional and genetic differences that contribute to mucosal defenses against bacterial pathogens. In the first aim, we will thoroughly characterize oral Salmonella infection in C57BL/6, 129S1 and A/J mice, through quantification of bacterial burden, quantitative histology, molecular assays of key immunological factors, and immunological assays of T and B lymphocyte responses. These studies will identify molecular and immunological factors that correlate with the control of bacterial replication and inflammation. In the second aim, we will identify A/J chromosomes that contribute to early cecal colonization and increased inflammation in A/J mice, using a panel of consomic mice, which harbor single A/J chromosomes on the C57BL/6 background. These studies will systematically define genetic differences between A/J and C57BL/6 mice that control mucosal immune defenses against Salmonella. Both of these aims will lead to the identification of novel molecular pathways, candidate genes and chromosomal loci that influence mucosal immunity. In this proposal, we will perform detailed studies to characterize molecular and genetic factors that regulate mucosal infection and inflammation. Our results will provide insight and pave the way for future studies aimed at developing a detailed model of mucosal defense to infection, improve mucosal vaccines, and treat intestinal inflammatory disorders. These studies should reveal mechanisms that control tolerance to commensal bacteria in the setting of infections, and permit the acquisition of specific and effective immunity to mucosal pathogens. Though many questions remain to be answered about mucosal immunity, this model system provides a valuable opportunity to dissect the contribution genetic factors from both host and pathogen to the control of persistent bacterial infections and mucosal inflammation.

描述（由申请人提供）：粘膜免疫系统必须同时从无害的菌群中解密病原体并保持自耐力，同时促进对病原体的长期免疫力。在肠道，尤其是大肠中，这是一项相当大的任务，共生微生物每克含量约为1012个细胞。我们已经表征了C57BL/6，A/J和129S1小鼠的沙门氏菌的口服感染，并证明了这种感染朝着3种不同的结果发展。 C57BL/6小鼠逐渐发展出盲肠感染，但被全身感染迅速淹没。 A/J小鼠在盲肠中迅速定植，然后慢性持续感染和炎症。 129S1小鼠逐渐发展出盲肠感染和炎症，并继续解决感染和炎症。我们假设宿主遗传差异是这些不同结果的主要决定因素。在此提案中，我们将使用两种规律的方法来破译重要的功能和遗传差异，从而有助于针对细菌病原体的粘膜防御。在第一个目的中，我们将通过定量细菌负担，定量组织学，关键免疫学因素的分子测定以及T和B淋巴细胞反应的免疫学测定法，以C57BL/6、129S1和A/J小鼠的口服沙门氏菌感染进行彻底表征。这些研究将确定与细菌复制和炎症控制相关的分子和免疫学因素。在第二个目的中，我们将使用一组综合小鼠面板确定A/J染色体有助于早期的盲肠定植并增加A/J小鼠的炎症，后者在C57BL/6背景上携带单个A/J染色体。这些研究将系统地定义控制粘膜免疫防御沙门氏菌的A/J和C57BL/6小鼠之间的遗传差异。这两个目标都将导致鉴定出影响粘膜免疫力的新分子途径，候选基因和染色体基因座。在此提案中，我们将进行详细的研究，以表征调节粘膜感染和炎症的分子和遗传因素。我们的结果将为未来的研究提供洞察力，旨在开发一种详细的粘膜防御模型以感染，改善粘膜疫苗和治疗肠道炎症性疾病。这些研究应揭示在感染中控制对共生细菌的耐受性的机制，并允许获得对粘膜病原体的特定和有效免疫。尽管有关粘膜免疫的许多问题仍有待回答，但该模型系统提供了一个宝贵的机会，可以从宿主和病原体中剖析遗传因素，以控制持续的细菌感染和粘膜炎症。

项目成果

FlgM is required to evade NLRC4-mediated host protection against flagellated Salmonella.

FlgM 需要逃避 NLRC4 介导的针对有鞭毛沙门氏菌的宿主保护。

• DOI: 10.1128/iai.00255-23
• 发表时间: 2023
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: López-Yglesias,AméricoHarry;Lu,Chun-Chi;Lai,MarvinA;Quarles,EllenK;Zhao,Xiaodan;Hajjar,AdelineM;Smith,KellyD
• 通讯作者: Smith,KellyD