Abstract
Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU) mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16), a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1) gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1Ity16/Ity16 mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1Ity16/Ity16 mutant mice demonstrated low levels of hepcidin (Hamp) expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15), erythropoietin (Epo) and heme oxygenase 1 (Hmox1) exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1Ity16/Ity16, the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1+/Ity16 mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1Ity16/Ity16 and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1+/Ity16 mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1 +/Ity16 heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are crucial in the host response to Salmonella infection in Ank1 mutants.
Highlights
Salmonella infections in humans are responsible for two major diseases, typhoid fever caused by Salmonella Typhi and Salmonella Paratyphi and a diarrheal disease known as salmonellosis caused by several non host specific serotypes including Salmonella Typhimurium and Salmonella Enteritidis
We report here the identification of a novel mutation (Ity16) in the gene ankyrin 1 (Ank1) identified in an ENU recessive screen for susceptibility to typhoid-like disease in mice
The mutation consists in a nonsense mutation (p.Gln1357Ter) located in the spectrin binding domain of Ank1
Summary
Salmonella infections in humans are responsible for two major diseases, typhoid fever caused by Salmonella Typhi and Salmonella Paratyphi and a diarrheal disease known as salmonellosis caused by several non host specific serotypes including Salmonella Typhimurium and Salmonella Enteritidis. Typhoid is transmitted by a fecal-oral route through contaminated food and water and is endemic in areas of poor water sanitation It is estimated by the World Health Organization that there are 21 million new cases of typhoid fever each year resulting in approximately 200,000 deaths. The study of the natural variation of the host response to infection with Salmonella Typhimurium in spontaneous mouse mutants have identified important innate immune genes having Mendelian contribution to disease susceptibility and contributing to different mechanisms including pathogen recognition (Tlr4P712H in C3H/HeJ), phagosome transport of divalent cations including iron (Nramp1G169D in C57BL/6J and BALB/cJ) or erythropoiesis and iron metabolism (PklrI90N in AcB61 mice) [7,8,9,10]
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