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.

抽象的： 在健康的个体中，非细类沙门氏菌血清型（NTS）与胃肠炎有关 死亡率低的局部感染表现为腹泻，呕吐和肠梗阻。然而， 长期以来，某些人口一直在增加威胁生命的系统性的风险增加 感染，包括非常年轻的感染，感染了艾滋病毒的感染以及接受癌症化学疗法的个体。 在这些个体中，NTS感染与菌血症有关，可以发展为脑膜炎和 败血症，常常有致命的结果。在撒哈拉以南非洲，目前有传播的NTS流行 感染，流行病学关联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的影响 感染知之甚少，尚不清楚哪些特定的营养缺乏症是负责的。之一 撒哈拉以南非洲儿童中最普遍的微量营养素缺陷是维生素A缺乏症。 但是，尚不清楚维生素A缺乏症是否会使个人容易散布NTS 感染，如果是这样，基本机制是什么。鉴于维生素负担很高，因此 撒哈拉非洲，这种知识的差距很重要，因为它可以提供干预措施来减少 幼儿传播NTS感染的发展。我们的实验证据表明这 微量营养素通过其活性代谢物维甲酸，对于防止在全身上复制NT是必不可少的 站点。此外，我们已经表明，维生素A缺陷小鼠在期间无法产生成熟的中性粒细胞 NTS感染。基于这些初步结果，本应用程序的总体目标是定义 维生素A依赖性免疫机制控制了传播NTS感染的发展，并 探索维生素A给药的可行性作为抗生素耐药NTS的辅助性 感染。拟议的工作具有很高的创新性，因为营养不良会影响的特定机制 对侵入性NTS疾病的敏感性尚不清楚。条件易于传播的事实 NTS感染被研究了，尽管它们代表了撒哈拉以南非洲死亡的主要原因，但 使拟议的工作非常重要。我们希望拟议的研究将提供重要的新 对控制侵入性NTS疾病很重要的特定免疫机制的见解，这可能 延伸至其他细菌的全身感染。因此，我们拟议的研究的结果是 可能提供新的范式，说明宿主中的潜在条件如何影响感染的结果。