Systemic infections with non-typhoidal Salmonella

非伤寒沙门氏菌全身感染

• 批准号: 9238432
• 负责人: Renee M Tsolis
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-12 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238432
• 关键词: Address; Affect; Africa South of the Sahara; African; Age; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Biology; Blood Circulation; Bone Marrow; Cessation of life; Chemotherapy-Oncologic Procedure; Child; Childhood; Defect; Development; Diarrhea; Disease; Emergency Situation; Epidemic; Epidemiology; Exploratory/Developmental Grant; Fatal Outcome; Focal Infection; Gastroenteritis; Generations; Granulopoiesis; HIV; Immune; Immune response; Immunity; Immunocompetent; Individual; Infection; Intervention; Intestines; Knowledge; Life; Malaria; Malnutrition; Meningitis; Micronutrients; Multi-Drug Resistance; Mus; Muscle Cramp; Nutrient; Outcome; Pathogenesis; Population; Predisposition; Research; Risk; Risk Factors; Role; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Sepsis; Serotyping; Site; Systemic infection; Testing; Tretinoin; Typhoid Fever; Vitamin A; Vitamin A Deficiency; Vomiting; Work; base; expectation; improved outcome; innovation; insight; killings; micronutrient deficiency; mortality; mouse model; neutrophil; novel; prevent; response

ABSTRACT: In healthy individuals, non-typhoidal Salmonella enterica serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, certain populations have long been known to be at increased risk of developing life-threatening systemic infections, including the very young, those infected with HIV, and individuals undergoing cancer chemotherapy. In these individuals, NTS infections are associated with bacteremia, which can progress to meningitis and sepsis, often with a fatal outcome. In sub-Saharan Africa, there is currently an epidemic of disseminated NTS infections, for which epidemiological associations suggest that the principal underlying factors in children are young age, malaria and malnutrition. The basis for the effect of malnutrition on the outcome of Salmonella infection is poorly understood, and it is unknown which specific nutrient deficiencies are responsible. One of the most widespread micronutrient deficiencies in sub-Saharan African children is vitamin A deficiency. However, it is unknown whether vitamin A deficiency renders individuals susceptible to disseminated NTS infection, and if so, what the underlying mechanisms are. Given the high burden of Vitamin A deficiency in sub- Saharan Africa, this gap in knowledge is important to address, as it could provide an intervention to reduce development of disseminated NTS infection in young children. Our experimental evidence suggests that this micronutrient, via its active metabolite, retinoic acid, is essential for preventing replication of NTS at systemic sites. Further, we have shown that vitamin A-deficient mice are unable to generate mature neutrophils during NTS infection. Based on these preliminary results, the overall objectives of this application are to define Vitamin A-dependent immune mechanisms that control development of disseminated NTS infection, and to explore feasibility of vitamin A administration as a adjunct to antibiotic treatment of multidrug resistant NTS infection. The proposed work is highly innovative since specific mechanisms by which malnutrition affects susceptibility to invasive NTS disease are not known. The fact that conditions predisposing to disseminated NTS infections are understudied, even though they represent a major cause of mortality in sub-Saharan Africa, makes the proposed work highly significant. We expect that the proposed research will provide important new insights into specific immune mechanisms that are important for controlling invasive NTS disease, that may extend to systemic infections with other bacteria as well. Therefore, the outcome of our proposed research is likely to provide novel paradigms of how underlying conditions in the host affect the outcome of an infection.

摘要： 在健康个体中，非伤寒性肠道沙门氏菌血清型（NTS）与胃肠炎相关， 局部感染，死亡率低，表现为腹泻、呕吐和肠痉挛。然而，在这方面， 长期以来，已知某些人群发生危及生命的系统性心脏病的风险增加， 感染者，包括非常年轻的人，感染艾滋病毒的人和正在接受癌症化疗的人。 在这些人中，NTS感染与菌血症有关，菌血症可进展为脑膜炎， 脓毒症，通常具有致命的结果。在撒哈拉以南非洲地区，目前有一种传播性NTS的流行病 感染，流行病学协会表明，儿童的主要潜在因素是 年轻、疟疾和营养不良。营养不良对沙门氏菌结果影响的基础 对感染的了解很少，也不知道具体是哪些营养素缺乏造成的。之一 撒哈拉以南非洲儿童最普遍的微量营养素缺乏症是维生素A缺乏症。 然而，维生素A缺乏是否使个体易患播散性NTS尚不清楚。 感染，如果是的话，潜在的机制是什么。由于维生素A缺乏的高负担， 在撒哈拉非洲，这一知识差距必须加以解决，因为它可以提供干预措施， 在幼儿中发生播散性NTS感染。我们的实验证据表明， 微量营养素，通过其活性代谢产物，视黄酸，是必不可少的，以防止复制的NTS在全身 网站.此外，我们已经证明，维生素A缺乏的小鼠在生长过程中不能产生成熟的中性粒细胞。 NTS感染。基于这些初步结果，本申请的总体目标是定义 维生素A依赖性免疫机制控制播散性NTS感染的发展， 探索维生素A作为抗生素治疗多药耐药NTS的辅助治疗的可行性 感染拟议的工作具有高度创新性，因为营养不良影响 对侵袭性NTS疾病易感性尚不清楚。事实上，条件诱发传播 尽管NTS感染是撒哈拉以南非洲地区死亡的主要原因， 这使得这项工作非常重要。我们希望这项研究将提供重要的新信息。 深入了解对控制侵袭性NTS疾病很重要的特定免疫机制， 也会扩展到其他细菌的全身感染。因此，我们提出的研究结果是 可能提供宿主的潜在条件如何影响感染结果的新范例。