Pathogenesis of Salmonella Bacteremia

University Of California At Davis, Davis CA

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Abstract

ABSTRACT In developed countries, non-typhoidal Salmonella enterica serotypes (NTS) are most commonly associated with gastroenteritis. However, certain populations, such as the very young and those with HIV, are at increased risk of bloodstream infection, a rare but life-threatening complication. In contrast to the developed world, in sub-Saharan Africa NTS infections are currently a leading cause of bloodstream infection and have a mortality rate of >20% in children. Epidemiological associations suggest that an important underlying factor in children is malnutrition, yet, the mechanisms by which malnutrition affects susceptibility to disseminated NTS infection are unknown. Vitamin A deficiency is one of the most widespread childhood micronutrient deficits. However, it is not known whether vitamin A deficiency predisposes malnourished children to disseminated NTS infection, and if so, what the underlying mechanisms are. Based on our preliminary results showing that Vitamin A deficiency compromises control of disseminated NTS infection, we propose to define Vitamin A-dependent immune mechanisms that control development of invasive disease. Our central hypothesis is that vitamin A deficiency compromises systemic control of disseminated NTS infection by impairing SLC11A1-dependent bacteriocidal mechanisms of neutrophils. The approach we will use to test and refine our hypothesis comprises three interrelated aims: (1) Define the role of SLC11A1/NRAMP1 in neutrophil-mediated control of disseminated NTS infection, (2) Explain how vitamin A deficiency impairs neutrophil-dependent clearance of S. Typhimurium, and (3) Determine whether vitamin A can be used therapeutically to improve treatment outcomes of infection with multiple drug-resistant NTS. We expect that the proposed research will deliver an important conceptual advance, by defining a new role for SLC11A1 in neutrophil-mediated control of disseminated NTS infection, and by establishing a mechanistic link between vitamin A status and antibacterial function of neutrophils. Further, our proposed studies have the potential to provide a novel, low-tech intervention against disseminated infection with drug- resistant NTS that can be implemented in resource-limited settings. Hence, successful completion of the proposed work will mark a decisive conceptual advance in understanding how malnutrition predisposes to NTS bacteremia, that will help to develop new interventions to combat the substantial mortality caused by this comorbidity in the developing world.