Salmonella entericaCauses More Severe Inflammatory Disease in C57/BL6Nramp1G169Mice Than Sv129S6 Mice

Brown, Diane E.; Libby, Stephen J.; Moreland, Sarah M.; McCoy, Melissa W.; Brabb, Thea; Stepanek, Aaron M; Fang, Ferric C.; Detweiler, Corrella S.

doi:10.1177/0300985813478213

Cited by 46 publications

(58 citation statements)

References 42 publications

(74 reference statements)

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“…We previously reported reduced tissue iron histochemical staining in resistant (Sv129S6 and C57/BL6 Nramp1 G169 ) mice infected with S. Typhimurium that became acutely anemic; Prussian blue staining of ferric iron in the spleen was scored at 3 to 4ϩ (on a scale of 0 to 4) in red pulp reticuloendothelial cells of control mice compared to 0 to 1ϩ in infected mice (7,8). While infection with S. Typhimurium causes mice to become anemic, the apparent decrease in tissue iron differs from classic AID (23).…”

Section: Quantification Of Reduced Splenic Iron In Infected Micementioning

confidence: 99%

“…For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6)(7)(8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by peripheral blood neutrophilia and monocytosis, bone marrow myeloid hyperplasia and hemophagocytosis, and splenomegaly secondary to extramedullary hematopoiesis (EMH) and phagocyte infiltration (7,8).…”

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confidence: 99%

“…Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6)(7)(8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by peripheral blood neutrophilia and monocytosis, bone marrow myeloid hyperplasia and hemophagocytosis, and splenomegaly secondary to extramedullary hematopoiesis (EMH) and phagocyte infiltration (7,8). The bacteria reside within tissue macrophages (6,9) and hemophagocytic macrophages (10,56), which have phagocytosed intact erythrocytes and leukocytes.…”

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confidence: 99%

“…Infected mice develop microcytic anemia that is most severe 1 to 3 weeks postinfection and persistent for 9 weeks, along with erythrocyte fragmentation and severely diminished tissue iron staining from 1 to 6 weeks postinfection (7,8). These hematopathological findings are characteristic features of systemic iron deficiency (22).…”

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Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

et al. 2015

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e The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-␥) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-␣])and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection.T yphoid fever is acquired upon oral ingestion of food or water contaminated with Salmonella enterica serovar Typhi or Paratyphi and remains a serious threat to public health, especially in developing countries (1). Human typhoid fever causes a broad range of clinical signs, including splenomegaly, neuropathy, and hematopathology, such as cytopenias (2), that have been modeled in laboratory mice infected with Salmonella enterica serovar Typhimurium (3). Inbred mouse strains with differing genetic backgrounds are characterized as either sensitive or resistant to S. Typhimurium. Sensitivity to the intracellular bacterial infection is caused by genetic deficiencies in the innate or adaptive immune system (4, 5). For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6-8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by periph...

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Section: Quantification Of Reduced Splenic Iron In Infected Micementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

et al. 2015

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“…For instance, during acute or chronic immune activation, ferritinbound iron accumulates in macrophages, a process that withholds iron from extracellular pathogens and is characteristic of the anemia of chronic disease (14,16). In contrast, macrophages infected with Salmonella increase the export of iron, and the spleen and liver of Salmonella-infected mice do not accumulate iron (17)(18)(19). Decreased iron concentrations in macrophages limit Salmonella replication (20,21), highlighting the importance of delineating how Salmonella acquires iron under such starved conditions.…”

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The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

et al. 2013

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bMost bacterial pathogens require iron to grow and colonize host tissues. The Gram-negative bacterium Salmonella enterica serovar Typhimurium causes a natural systemic infection of mice that models acute and chronic human typhoid fever. S. Typhimurium resides in tissues within cells of the monocyte lineage, which limit pathogen access to iron, a mechanism of nutritional immunity. The primary ferric iron import system encoded by Salmonella is the siderophore ABC transporter FepBDGC. The Fep system has a known role in acute infection, but it is unclear whether ferric iron uptake or the ferric iron binding siderophores enterobactin and salmochelin are required for persistent infection. We defined the role of the Fep iron transporter and siderophores in the replication of Salmonella in macrophages and in mice that develop acute followed by persistent infections. Replication of wild-type and iron transporter mutant Salmonella strains was quantified in cultured macrophages, fecal pellets, and host tissues in mixed-and single-infection experiments. We show that deletion of fepB attenuated Salmonella replication and colonization within macrophages and mice. Additionally, the genes required to produce and transport enterobactin and salmochelin across the outer membrane receptors, fepA and iroN, are needed for colonization of all tissues examined. However, salmochelin appears to be more important than enterobactin in the colonization of the spleen and liver, both sites of dissemination. Thus, the FepBDGC ferric iron transporter and the siderophores enterobactin and salmochelin are required by Salmonella to evade nutritional immunity in macrophages and cause persistent infection in mice.

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Salmonella Meningitis Associated with Monocyte Infiltration in Mice

Bauler

Starr

Nagy

et al. 2017

The American Journal of Pathology

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In the current study, we examined the ability of Salmonella enterica serovar Typhimurium to infect the central nervous system and cause meningitis following the natural route of infection in mice. C57BL/6J mice are extremely susceptible to systemic infection by Salmonella Typhimurium because of loss-of-function mutations in Nramp1 (SLC11A1), a phagosomal membrane protein that controls iron export from vacuoles and inhibits Salmonella growth in macrophages. Therefore, we assessed the ability of Salmonella to disseminate to the central nervous system (CNS) after oral infection in C57BL/6J mice expressing either wild-type (resistant) or mutant (susceptible) alleles of Nramp1. In both strains, oral infection resulted in focal meningitis and ventriculitis with recruitment of inflammatory monocytes to the CNS. In susceptible Nramp1 mice, there was a direct correlation between bacteremia and the number of bacteria in the brain, which was not observed in resistant Nramp1 mice. A small percentage of Nramp1 mice developed severe ataxia, which was associated with high bacterial loads in the CNS as well as clear histopathology of necrotizing vasculitis and hemorrhage in the brain. Thus, Nramp1 is not essential for Salmonella entry into the CNS or neuroinflammation, but may influence the mechanisms of CNS entry as well as the severity of meningitis.

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Salmonella entericaCauses More Severe Inflammatory Disease in C57/BL6Nramp1^G169Mice Than Sv129S6 Mice

Cited by 46 publications

References 42 publications

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

Salmonella Meningitis Associated with Monocyte Infiltration in Mice

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