Nutritional immunity during Salmonella infection

沙门氏菌感染期间的营养免疫

• 批准号: 10736878
• 负责人: Manuela Raffatellu
• 金额: $ 46.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736878
• 关键词: Affinity; Bacteria; Bile Acids; Colitis; Complex; Enabling Factors; Enterobacteriaceae; Environment; Epithelial Cells; Escherichia coli; Ferrichrome; Fluorescent in Situ Hybridization; Gastrointestinal tract structure; Goals; Homeostasis; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory Response; Integration Host Factors; Iron; LCN2 gene; Laboratories; Leukocyte L1 Antigen Complex; Manganese; MccJ25; Metabolic; Metagenomics; Metals; Microbe; Modeling; Morbidity - disease rate; Mucous Membrane; Neutrophil Infiltration; Nutrient; Nutritional; Nutritional Immunity; Pathogenesis; Periodicity; Probiotics; Process; Production; Proteins; Research; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Side; System; T-Lymphocyte; Testing; Virulence Factors; Work; Zinc; acquired immunity; antimicrobial; antimicrobial peptide; beneficial microorganism; cytokine; gut inflammation; gut microbiome; gut microbiota; in vivo; interleukin-22; metatranscriptomics; microbial; microbiota; microcin; mortality; non-typhoidal Salmonella; novel strategies; pathogen; receptor; response; yersiniabactin

SUMMARY Non-typhoidal Salmonella (NTS) causes 100 million infections per year worldwide. The pathogen infects the gastrointestinal tract, where it triggers intestinal inflammation. Essential to NTS pathogenesis is the ability to evade host responses and compete with the gut microbiota. Research in my laboratory has contributed to elucidating the duality of the mucosal response to Salmonella enterica serovar Typhimurium (STm), a highly prevalent NTS serovar. Particularly, we have shown that STm evades sequestration of essential metal nutrients, a process known as “nutritional immunity”, to thrive in the inflamed gut and compete with the microbiota. We discovered: (i) key host factors that modulate nutritional immunity in the inflamed gut, including the cytokine interleukin-22 (IL-22) and the antimicrobial proteins lipocalin-2 and calprotectin; (ii) several mechanisms and virulence factors that enable STm to overcome metal nutrient sequestration in the inflamed gut. We also discovered that, during colitis, the probiotic bacterium Escherichia coli Nissle 1917 (EcN) competes with STm for iron and zinc via multiple mechanisms, including expression of high affinity iron and zinc acquisition systems, and secretion of small antimicrobial molecules termed microcins. Building on this prior work, the primary objective of this application is to continue to investigate host-microbe and microbe-microbe interaction in the inflamed gut, a complex environment with unique nutritional challenges for both pathogens and the microbiota. We will continue to investigate the role of microcins and zinc acquisition systems in the inflamed gut, and we will expand to elucidating the role of secondary bile acids, including newly discovered microbial conjugated bile acids, in modulating nutritional immunity. Our central hypothesis is that the host inflammatory response changes the nutritional and metabolic landscape of the gut, triggering an environment that favors the bloom of Enterobacteriaceae and promotes microbial competition. In Aim 1, we will elucidate mechanisms of competition for metal nutrients in the inflamed gut between Salmonella, E. coli Nissle, and the gut microbiota. In Aim 2, we will evaluate the impact of Salmonella infection on bile acid pool composition, and the impact of these changes on nutritional immunity. Understanding the host and microbial factors that modulate host immunity, together with the mechanisms by which STm thrives in this environment, is essential for developing new approaches to limit STm replication in the inflamed gut.

概括 非细类沙门氏菌（NTS）每年在全球引起1亿个感染。病原体感染 胃肠道，它触发肠道注射。 NTS发病机理必不可少的是 逃避宿主反应并与肠道菌群竞争。我的实验室的研究促成了 阐明粘膜对沙门氏菌血清Typhimurium（STM）的二元反应，高度 普遍的NTS血清。特别是，我们已经表明，STM逃避了必需金属养分的固执， 一种称为“营养免疫力”的过程，在发炎的肠道中壮成长并与微生物群竞争。我们 发现：（i）调节发炎肠道营养免疫的关键宿主因素，包括细胞因子 白细胞介素22（IL-22）和抗菌蛋白脂肪蛋白-2和钙蛋白钙蛋白酶蛋白； （ii）几种机制和 毒力因子使STM能够克服发炎的肠道中的金属养分隔离。我们也是 发现，在结肠炎期间，益生菌大肠杆菌Nissle 1917（ECN）与STM竞争 对于铁和锌通过多种机制，包括高亲和力铁和锌采集系统的表达， 和称为微蛋白的小抗菌分子的分泌。在这项先前的工作中，主要目标 该应用程序是继续研究发炎的肠道中的宿主微生物和微生物 - 微生物相互作用， 一个复杂的环境，对病原体和微生物群都有独特的营养挑战。我们将 继续研究微蛋白和锌采集系统在发炎的肠道中的作用，我们将扩展 阐明次生胆汁酸的作用，包括新发现的微生物共轭胆汁酸 调节营养免疫。我们的中心假设是宿主炎症反应改变了 肠道的营养和代谢景观，触发了有利于盛开的环境 肠杆菌科并促进微生物竞争。在AIM 1中，我们将阐明竞争机制 用于沙门氏菌，大肠杆菌和肠道菌群之间发炎的肠道中的金属营养素。在AIM 2中，我们 将评估沙门氏菌感染对胆汁酸池组成的影响，以及这些变化的影响 营养免疫。了解调节宿主免疫力的宿主和微生物因子以及 STM在这种环境中蓬勃发展的机制对于开发新方法至关重要 发炎的肠道中的STM复制。

项目成果

Harnessing Iron Acquisition Machinery to Target Enterobacteriaceae.

利用铁获取机制来瞄准肠杆菌科细菌。

• DOI: 10.1093/infdis/jiaa440
• 发表时间: 2021
• 期刊: The Journal of infectious diseases
• 作者: Sargun,Artur;Gerner,RomanaR;Raffatellu,Manuela;Nolan,ElizabethM
• 通讯作者: Nolan,ElizabethM

Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella.

• DOI: 10.1021/acsinfecdis.1c00005
• 发表时间: 2021-05-14
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Sargun A;Sassone-Corsi M;Zheng T;Raffatellu M;Nolan EM
• 通讯作者: Nolan EM

Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching.

• DOI: 10.1038/s43587-022-00187-y
• 发表时间: 2022-03
• 期刊: NATURE AGING
• 作者: Mkhikian, Haik;Hayama, Ken L.;Khachikyan, Khachik;Li, Carey;Zhou, Raymond W.;Pawling, Judy;Klaus, Suzi;Tran, Phuong Q. N.;Ly, Kim M.;Gong, Andrew D.;Saryan, Hayk;Hai, Jasper L.;Grigoryan, David;Lee, Philip L.;Newton, Barbara L.;Raffatellu, Manuela;Dennis, James W.;Demetriou, Michael
• 通讯作者: Demetriou, Michael

Microcins mediate competition among Enterobacteriaceae in the inflamed gut.

• DOI: 10.1038/nature20557
• 发表时间: 2016-12-08
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Sassone-Corsi, Martina;Nuccio, Sean-Paul;Liu, Henry;Hernandez, Dulcemaria;Vu, Christine T.;Takahashi, Amy A.;Edwards, Robert A.;Raffatellu, Manuela
• 通讯作者: Raffatellu, Manuela