Vitamin A deficiency impairs neutrophil-mediated control of Salmonella via SLC11A1 in mice
Kristen L. Lokken-Toyli, Vladimir E. Diaz-Ochoa, Lizbeth Camacho, Annica R. Stull-Lane, Amber E. R. Van Hecke, Jason P. Mooney, Ariel Del Hoyo Muñoz, G. Walker, Daniela Hampel, Xiaowen Jiang, Jasmine C. Labuda, Claire E. Depew, Stephen J. McSorley, Charles B. Stephensen, Renée M. Tsolis
Abstract
Abstract In sub-Saharan Africa, multidrug-resistant non-typhoidal Salmonella serovars are a common cause of fatal bloodstream infection. Malnutrition is a predisposing factor, but the underlying mechanisms are unknown. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated non-typhoidal Salmonella disease in mice and impairs terminal neutrophil maturation. Immature neutrophils had reduced expression of Slc11a1 , a gene that encodes a metal ion transporter generally thought to restrict pathogen growth in macrophages. Adoptive transfer of SLC11A1-proficient neutrophils, but not SLC11A1-deficient neutrophils, reduced systemic Salmonella burden in Slc11a1 −/− mice or mice with vitamin A deficiency. Loss of terminal granulopoiesis regulator CCAAT/enhancer-binding protein ϵ (C/EBPϵ) also decreased neutrophil-mediated control of Salmonella , but not that mediated by peritoneal macrophages. Susceptibility to infection increased in Cebpe −/− Slc11a1 +/+ mice compared with wild-type controls, in an Slc11a1 -expression-dependent manner. These data suggest that SLC11A1 deficiency impairs Salmonella control in part by blunting neutrophil-mediated defence.