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.

Public Health Relevance

Invasive disease with non-typhoidal Salmonella (NTS) is responsible for nearly 700,000 deaths annually. In sub-Saharan Africa, the majority of bloodstream isolates in children are antibiotic-resistant NTS, and a major childhood risk factor in African children for developing systemic NTS infection is malnutrition. This application will use mice to study how a widespread nutrient deficiency in sub-Saharan Africa, vitamin A deficiency, affects susceptibility to invasive disease, and will explore the utility of vitamin A to supplement treatment of antibiotic- resistant NTS disease. These studies will be important, as they have the potential both to uncover new basic information on why malnutrition makes children more susceptible to infection, and to provide a new strategy to treat malnourished children suffering from invasive infections with multiple antibiotic-resistant NTS.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Alexander, William A
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University of California Davis
Schools of Medicine
United States
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