Host defense against Shigella flexneri

宿主对福氏志贺氏菌的防御

• 批准号: 10601092
• 负责人: Zannatun Noor
• 金额: $ 7.46万
• 依托单位: INTERNATIONAL CTR/DIARRHOEAL DIS RES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-27 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601092
• 关键词: 2 year old; 5 year old; Actins; Acute; Address; Age; Animal Model; Annual Reports; Antimicrobial Resistance; Bacteria; Bacterial Antibiotic Resistance; Bangladesh; Biological; Biopsy; Cell physiology; Cells; Cellular Infiltration; Cessation of life; Child; Child Health; Ciprofloxacin; Collaborations; Colon; Communicable Diseases; Convalescence; Development; Diarrhea; Drug resistance; Dysentery; Environment; Epithelial Cells; Flow Cytometry; Foundations; Gene Expression; Genes; Goals; Histologic; Host Defense; Human; IL8 gene; Immune; Immune response; Immunology; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Intervention; Invaded; K-Series Research Career Programs; Knowledge; Life; Link; Memory; Mentors; Multi-Drug Resistance; NF-kappa B; Oral; Outcome; Pathway Analysis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Phosphotransferases; Population; Predisposition; Prevention; Production; Program Development; Proteins; Reporting; Research; Research Personnel; Resistance; Role; Scientist; Serotyping; Severities; Shigella; Shigella Infections; Shigella flexneri; Signal Transduction; Site; Supervision; Technology; Testing; Therapeutic; Tissues; Training; Type III Secretion System Pathway; United States; Universities; Vaccines; Virginia; antimicrobial; azithromycin resistance; career; career development; cell motility; clinical investigation; cytokine; design; experience; genetic signature; immune cell infiltrate; innovation; intestinal epithelium; low and middle-income countries; low income country; molecular diagnostics; pathogen; resistant strain; response; success; targeted treatment; therapeutic target; trafficking; transcriptome; transcriptome sequencing

Project Summary Our Objective: To understand the host response to S. flexneri infection in developing potential host directed therapeutics. Hypothesis: Host genes and cellular processes are essential for efficient colonization and dissemination of S. flexneri in the human colon. These genes and cell processes can be discovered by comparing colonic biopsies during acute shigellosis to convalescence. Significance: Approximately 165 million cases of shigellosis are annually reported in low-income countries, with at least 1 million of these cases resulting in death, especially in children under five years of age (5). Very recently, Shigella ranked the highest among the overall pathogen burden, with a particularly high incidence in the second year of life (10). As is well known to CDC, multidrug resistant Shigella infections are a “serious” threat (18). Currently, no effective vaccine with the ability to confer adequate protection against the many different serotypes of Shigella has been developed. Investigators: Dr. Zannatun Noor is an early career research scientist from Bangladesh and seeking a mentored research career development award. She will conduct the study under supervision of Bangladesh mentor Dr. Rashidul Haque at icddr, b and USA mentor Dr. William A. Petri at University of Virginia. Both mentors are working with collaboration for more than two decades and have successfully completed different studies. Innovation: Determine gene expression and cellular infiltration to identify the host immune response is ground-breaking in Shigellosis. We will conduct RNAseq and CyTOF of colon biopsies to determine host gene expression and cellular infiltration respectively. Approach: To test our hypothesis, our specific aims are- 1) Systematically determine and characterize colonic gene expression profiles in response to S. flexneri infection. 2) Determine the identity of infiltrating immune cells in the colon during S. flexneri infection vs convalescence. Environment: Key to success of the study are the experienced mentors and highly motivated candidate who is seeking for the necessary training, practical experience, and knowledge to become a leading independent investigator in implementing child health interventions to reduce burden of infectious diseases in Low and Middle-Income Countries. Mentors are complementary expertise, like US mentor at the University of Virginia in immunology and in advance technology and LMIC mentor at icddr, b in clinical investigation. Both the host institute at LMIC and US institute have strong commitment to the candidate and her proposed career development.

项目摘要 我们的目标：了解宿主对福氏志贺氏菌感染的反应，以开发潜在的宿主 治疗学。 假设：宿主基因和细胞过程是有效定植和传播S。 人体结肠中的福氏杆菌。这些基因和细胞过程可以通过比较结肠活检来发现。 在急性志贺氏菌病到恢复期。 意义：低收入国家每年报告的志贺氏菌病病例约为1.65亿例， 其中至少有100万例导致死亡，特别是五岁以下儿童(5)。非常 最近，志贺氏菌在总病原菌负担中排名最高，在 生命的第二年(10岁)。正如疾控中心所熟知的，耐多药志贺氏菌感染是一种“严重”的疾病 威胁(18)。目前，没有一种有效的疫苗能够提供足够的保护，防止许多 志贺氏菌的不同血清型已经被开发出来。 调查人员：Zannatun Noor博士是来自孟加拉国的早期职业研究科学家，正在寻找 导师研究职业发展奖。她将在孟加拉国的监督下进行这项研究 ICDDR的导师拉希杜尔·哈克博士和弗吉尼亚大学的美国导师威廉·A·佩里博士。两者都有 导师从事协作工作已有二十多年，并成功地完成了不同的 学习。 创新：确定基因表达和细胞渗透以确定宿主的免疫反应 志贺氏菌病的开创性进展。我们将进行结肠活检的RNAseq和CyTOF来确定宿主基因 细胞分别呈阳性表达和细胞浸润。 方法：为了验证我们的假设，我们的具体目标是：1)系统地确定和表征结肠 福氏志贺菌感染后的基因表达谱。2)确定浸润性免疫的身份 福氏志贺氏菌感染与恢复期结肠细胞。 学习环境：成功学习的关键是经验丰富的导师和积极进取的候选人 寻求必要的培训、实践经验和知识，以成为领先的独立人士 调查员在实施儿童健康干预措施以减轻低收入和低收入人群传染病负担方面的工作 中等收入国家。导师是互补的专业知识，就像弗吉尼亚大学的美国导师 免疫学和先进技术和LMIC导师在ICDDR，b进行临床研究。这两个主机 LMIC研究所和美国研究所对候选人和她提出的职业生涯有着坚定的承诺 发展。