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.

总结 非伤寒沙门氏菌（NTS）每年在全球造成1亿人感染。病原体感染了 胃肠道，在那里它会引发肠道炎症。NTS发病机制的关键是 逃避宿主反应并与肠道菌群竞争。我实验室的研究 阐明了对肠道沙门氏菌鼠伤寒血清型（STm）的粘膜反应的双重性，这是一种高度免疫反应。 流行的NTS血清型。特别是，我们已经表明，STm逃避螯合的基本金属营养素， 这一过程被称为“营养免疫”，在发炎的肠道中茁壮成长，并与微生物群竞争。我们 发现：（i）调节炎症肠道营养免疫的关键宿主因子，包括细胞因子 白细胞介素-22（IL-22）和抗微生物蛋白脂质运载蛋白-2和钙卫蛋白;（ii）几种机制和 毒力因子，使STm克服金属营养螯合在发炎的肠道。我们也 发现，在结肠炎期间，益生菌大肠杆菌Nissle 1917（EcN）与STm竞争 通过多种机制，包括表达高亲和力的铁和锌获取系统， 和分泌称为微菌素的小抗微生物分子。在此基础上，主要目标 继续研究发炎肠道中宿主-微生物和微生物-微生物的相互作用， 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 我们将继续研究微菌素和锌获取系统在炎症肠道中的作用，我们将扩大 阐明次级胆汁酸，包括新发现的微生物结合胆汁酸， 调节营养免疫。我们的中心假设是宿主的炎症反应改变了 肠道的营养和代谢景观，引发了一个有利于开花的环境， 促进微生物竞争。在目标1中，我们将阐明竞争机制 沙门氏菌、E.大肠杆菌和肠道菌群。在目标2中， 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 关于营养免疫了解调节宿主免疫力的宿主和微生物因素，以及 STm在这种环境中蓬勃发展的机制，对于开发新的方法来限制 STm在发炎肠道中的复制。

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