The impact of ER stress on Salmonella Typhimurium infections

内质网应激对鼠伤寒沙门氏菌感染的影响

• 批准号: 10708073
• 负责人: Arina Marijke Keestra-Gounder
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708073
• 关键词: ATF6 gene; Actins; Apoptosis; Apoptotic; Autophagocytosis; Bacterial Infections; Binding; Biological Process; Calcium; Calcium Signaling; Cell Death Induction; Cell physiology; Cells; Colitis; Complex; Cytoskeleton; Data; Development; Endoplasmic Reticulum; Epithelial Cells; Functional disorder; Future; Gastroenteritis; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genes; Gram-Negative Bacteria; Homeostasis; Human; Immune response; Immune signaling; Immunologic Receptors; In Vitro; Induction of Apoptosis; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Intestines; Ligands; Link; Lipids; Mediating; Membrane; Modeling; Mus; Mutant Strains Mice; Mutation; Nutrient; Pathogenesis; Pathology; Pathway interactions; Pattern recognition receptor; Peptidoglycan; Play; Population; Predisposition; Process; Protein Inhibition; Proteins; Regulation; Resistance; Resources; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Signal Transduction; Source; Streptomycin; Testing; Therapeutic; Translations; Work; XBP1 gene; biological adaptation to stress; conditional mutant; dextran sulfate sodium induced colitis; endoplasmic reticulum stress; experimental study; gut inflammation; interest; intestinal epithelium; microbiota; monocyte; pathogen; protein complex; protein misfolding; receptor; release of sequestered calcium ion into cytoplasm; response; sphingosine 1-phosphate; tissue/cell culture

Project Summary NOD1 and NOD2 are Pattern Recognition Receptors that sense fragments of bacterial peptidoglycans, and are able to detect perturbations in cellular processes such as the regulation of the actin cytoskeleton and disturbance in endoplasmic reticulum (ER) homeostasis. Under different stressful conditions, such as bacterial infections, protein misfolding and perturbations in calcium homeostasis, the ER is unable to maintain homeostasis and activates the unfolded protein response (UPR). Within the UPR three transmembrane receptors, IRE1α, PERK and ATF6, are activated and regulate biological processes such as inhibition of protein translation, autophagy, and inflammation to reestablish cellular homeostasis. NOD1 and NOD2 have been implicated in ER stress- induced inflammation, by acting downstream of IRE1α in the UPR to induce inflammatory responses. This link between the UPR and NOD1/2 signaling is of particular interest in intestinal inflammation since mutations in genes associated with the UPR (XBP1) and innate immune signaling (NOD2) have been associated with intestinal epithelial cell (IEC) dysfunction in intestinal inflammatory diseases. Salmonella Typhimurium (S. Tm) is a gram-negative bacterium that induces robust inflammation, partially dependent on NOD1/2 activation, of the intestinal epithelium resulting in gastroenteritis. As a survival mechanism, S. Tm has adapted to these inflammatory conditions in the intestinal tract by utilizing products of inflammation as a nutrient source to outcompete the resident microbiota. Considering the importance of ER stress in intestinal inflammation and the fact that S. Tm is a major cause of gastroenteritis, it is surprising that ER stress in the context of Salmonella infections is significantly underexplored. Furthermore, it is currently unknown whether S. Tm can exploit ER stress-induced inflammation resulting in luminal expansion. Our objectives are to investigate the link between ER stress and inflammation in the S. Tm-induced colitis model. Our central hypothesis is that activation of the ER stress response in the gastrointestinal tract contributes significantly to S. Tm-induced inflammation, luminal expansion and pathology. We will test our hypothesis by pursuing the following three aims. 1) Determine the contribution of calcium flux and UPR activation to NOD1/2 signaling. In in vitro experiments we will determine which branches of the UPR, in conjunction with dysregulation of calcium signaling, contributes to NOD1/2 activation. 2) Determine the role of CHOP in the S. Tm-induced colitis model. Using Chop-/- mice and conditional mutant mice we will investigate the role of CHOP in S. Tm-induced inflammation and outgrowth. 3) Determine the role of NOD1/2 and IRE1α in response to S. Tm. We will investigate the role of IRE1α in Nod1/2-/- mice in the S. Tm-induced colitis model. Characterizing the mechanisms downstream of the UPR that orchestrate ER stress-induced responses is necessary to safely modulate this process for the development of future therapeutics and will significantly increase our understanding in Salmonella pathogenesis.

项目总结