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Systemic infections with non-typhoidal Salmonella

非伤寒沙门氏菌全身感染

基本信息

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
项目类别：
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

项目摘要

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.

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