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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #332210
Title: Vitamin A deficiency impairs neutrophil-mediated control of Salmonella via SLC11A1 in mice

Author
item LOKKEN-TOYLI, KRISTEN - University Of California, Davis
item DIAZ-OCHOA, VLADIMIR - University Of California, Davis
item CAMACHO, LIZBETH - University Of California, Davis
item STULL-LANE, ANNICA - University Of California, Davis
item VAN HECKE, AMBER - University Of California, Davis
item MOONEY, JASON - University Of California, Davis
item MUNOZ, ARIEL - University Of California, Davis
item WALKER, GREGORY - University Of California
item Hampel, Daniela
item Jiang, Xiaowen
item LABUDA, JASMINE - University Of California, Davis
item DEPEW, CLAIRE - University Of California, Davis
item MCSORLEY, STEPHEN - University Of California, Davis
item Stephensen, Charles
item TSOLIS, RENÉE - University Of California, Davis

Submitted to: Nature Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/18/2024
Publication Date: 2/19/2024
Citation: Lokken-Toyli, K.L., Diaz-Ochoa, V.E., Camacho, L., Stull-Lane, A.R., Van Hecke, A., Mooney, J.P., Munoz, A.D., Walker, G.T., Hampel, D., Jiang, X., Labuda, J.C., Depew, C.E., McSorley, S.J., Stephensen, C.B., Tsolis, R.M. 2024. Vitamin A deficiency impairs neutrophil-mediated control of Salmonella via SLC11A1 in mice. Nature Microbiology. 9:727–736. https://doi.org/10.1038/s41564-024-01613-0.
DOI: https://doi.org/10.1038/s41564-024-01613-0

Interpretive Summary: Vitamin A deficiency is known to increase the risk of death from infectious disease of childhood by impairing the immune response of malnourished children to pathogenic microorganisms. In particular, neutrophil function has been suspected to be impaired by vitamin A deficiency but the specific mechanism accounting for apparent defects in neutrophil development, and in their ability to kill bacteria, have not been examined in detail. In the present study we found that vitamin A deficient mice had relatively normal neutrophils when not challenged by an infection, but infection with Salmonella bacteria, a common human pathogen, led to production of immature neutrophils with diminished surface expression of Ly6G, a marker of neutrophil development. This impairment in Salmonella-induced development of neutrophils was accompanied by reduced formation of secondary granules, which contain proteins that help control bacterial infections. Supplementation of deficient mice with vitamin A provided before infection restored neutrophil maturation and improved subsequent control of Salmonella infection in deficient mice. Treatment with a single dose of vitamin A after infection was sufficient to reduce bacterial burden in the blood and spleen, suggesting that supplementation could be developed as a strategy to augment antibiotic therapy of Salmonella infection in malnourished children.

Technical Abstract: Non-typhoidal Salmonella (NTS) serovars normally cause a self-limited gastroenteritis, but individuals with underlying immunodeficiencies can develop a life threatening bacteremia. In sub-Saharan Africa, NTS serovars are among the most common causes of bloodstream infection. One condition predisposing African children to NTS bacteremia is malnutrition, but the underlying mechanism is not known. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated NTS disease in mice. Vitamin A-deficient (VAD) mice were unable to control systemic NTS infections early in the course of disease, suggesting a deficit in innate immunity. While neutrophils appeared normal in VAD mice prior to infection, NTS infection led to production of immature neutrophils with diminished surface expression of Ly6G. Impaired infection-induced granulopoiesis in VAD mice was accompanied by reduced secondary granule formation. Retinyl palmitate supplementation provided prophylactically prior to NTS infection restored neutrophil maturation and improved subsequent control of bacteria in VAD mice. Treatment with a single dose of retinyl palmitate after NTS infection was sufficient to reduce bacterial burden at systemic sites, suggesting that supplementation could be developed as a strategy to augment antibiotic therapy of NTS bacteremia in malnourished children.