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Dietary Manganese Promotes Staphylococcal Infection of the Heart.
Juttukonda LJ, Berends ETM, Zackular JP, Moore JL, Stier MT, Zhang Y, Schmitz JE, Beavers WN, Wijers CD, Gilston BA, Kehl-Fie TE, Atkinson J, Washington MK, Peebles RS, Chazin WJ, Torres VJ, Caprioli RM, Skaar EP
(2017) Cell Host Microbe 22: 531-542.e8
MeSH Terms: Abscess, Animals, Diet, Disease Models, Animal, Endocarditis, Bacterial, Heart, Humans, Leukocyte L1 Antigen Complex, Liver, Manganese, Mice, Mice, Congenic, Mice, Inbred C57BL, Neutrophils, Reactive Oxygen Species, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added March 14, 2018
Diet, and specifically dietary metals, can modify the risk of infection. However, the mechanisms by which manganese (Mn), a common dietary supplement, alters infection remain unexplored. We report that dietary Mn levels dictate the outcome of systemic infections caused by Staphylococcus aureus, a leading cause of bacterial endocarditis. Mice fed a high Mn diet display alterations in Mn levels and localization within infected tissues, and S. aureus virulence and infection of the heart are enhanced. Although the canonical mammalian Mn-sequestering protein calprotectin surrounds staphylococcal heart abscesses, calprotectin is not released into the abscess nidus and does not limit Mn in this organ. Consequently, excess Mn is bioavailable to S. aureus in the heart. Bioavailable Mn is utilized by S. aureus to detoxify reactive oxygen species and protect against neutrophil killing, enhancing fitness within the heart. Therefore, a single dietary modification overwhelms vital host antimicrobial strategies, leading to fatal staphylococcal infection.
Copyright © 2017 Elsevier Inc. All rights reserved.
0 Communities
4 Members
0 Resources
17 MeSH Terms
Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.
Erickson JJ, Lu P, Wen S, Hastings AK, Gilchuk P, Joyce S, Shyr Y, Williams JV
(2015) J Immunol 195: 4319-30
MeSH Terms: Acute Disease, Animals, CD8-Positive T-Lymphocytes, Cluster Analysis, Gene Expression Profiling, Host-Pathogen Interactions, Humans, Lung, Metapneumovirus, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Paramyxoviridae Infections, Phenotype, Programmed Cell Death 1 Receptor, Respiratory Tract Infections, Spleen, Transcriptome
Show Abstract · Added October 2, 2015
Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.
Copyright © 2015 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
19 MeSH Terms
G6PC2: a negative regulator of basal glucose-stimulated insulin secretion.
Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, O'Brien RM
(2013) Diabetes 62: 1547-56
MeSH Terms: Adiposity, Animals, Blood Glucose, Calcium Signaling, Diet, High-Fat, Female, Glucose-6-Phosphatase, Heterozygote, Insulin, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Kinetics, Male, Mice, Mice, Congenic, Mice, Knockout, Obesity, Pancreas, Proteins, Sex Characteristics
Show Abstract · Added July 21, 2014
Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.
2 Communities
3 Members
1 Resources
22 MeSH Terms
Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.
Zhang JJ, Malekpour M, Luo W, Ge L, Olaru F, Wang XP, Bah M, Sado Y, Heidet L, Kleinau S, Fogo AB, Borza DB
(2012) J Immunol 188: 3268-77
MeSH Terms: Albuminuria, Animals, Autoantibodies, Autoantigens, Basement Membrane, Collagen Type IV, Complement C3, Disease Models, Animal, Glomerulonephritis, Membranous, Immunization, Immunoglobulin G, Kidney, Mice, Mice, Congenic, Mice, Inbred DBA, Nephrotic Syndrome, Pulmonary Alveoli, Receptors, IgG, Recombinant Fusion Proteins
Show Abstract · Added August 21, 2013
Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII(-/-) and FcRγ(-/-) mice immunized with a fragment of α3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-α3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease.
Walters LC, Cantrell VA, Weller KP, Mosher JT, Southard-Smith EM
(2010) Hum Mol Genet 19: 4353-72
MeSH Terms: Animals, CD57 Antigens, Disease Models, Animal, Enteric Nervous System, Ganglia, Hirschsprung Disease, Humans, Immunohistochemistry, Intestine, Small, Intestines, Mice, Mice, Congenic, Mice, Inbred C3H, Mice, Inbred C57BL, Mutation, Neural Crest, SOXE Transcription Factors, Species Specificity, Stem Cells
Show Abstract · Added November 14, 2013
Abnormalities in the development of enteric neural crest-derived progenitors (ENPs) that generate the enteric nervous system (ENS) can lead to aganglionosis in a variable portion of the distal gastrointestinal tract. Cumulative evidence suggests that variation of aganglionosis is due to gene interactions that modulate the ability of ENPs to populate the intestine; however, the developmental processes underlying this effect are unknown. We hypothesized that differences in enteric ganglion deficits could be attributable to the effects of genetic background on early developmental processes, including migration, proliferation, or lineage divergence. Developmental processes were investigated in congenic Sox10(Dom) mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe). Immuno-staining on whole-mount fetal gut tissue and dissociated cell suspensions was used to assess migration and proliferation. Flow cytometry utilizing the cell surface markers p75 and HNK-1 was used to isolate live ENPs for analysis of developmental potential. Frequency of ENPs was reduced in Sox10(Dom) embryos relative to wild-type embryos, but was unaffected by genetic background. Both migration and developmental potential of ENPs in Sox10(Dom) embryos were altered by inbred strain background with the most highly significant differences seen for developmental potential between strains and genotypes. In vivo imaging of fetal ENPs and postnatal ganglia demonstrates that altered lineage divergence impacts ganglia in the proximal intestine. Our analysis demonstrates that genetic background alters early ENS development and suggests that abnormalities in lineage diversification can shift the proportions of ENP populations and thus may contribute to ENS deficiencies in vivo.
1 Communities
2 Members
0 Resources
19 MeSH Terms
Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin.
Kim I, Ding T, Fu Y, Li C, Cui L, Li A, Lian P, Liang D, Wang DW, Guo C, Ma J, Zhao P, Coffey RJ, Zhan Q, Wu G
(2009) J Am Soc Nephrol 20: 2556-69
MeSH Terms: Animals, Apoptosis, Cell Line, Cell Proliferation, Cysts, Disease Models, Animal, Female, Kidney Tubules, Collecting, Liver Diseases, Male, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Mutation, Pancreatic Diseases, Phenotype, Polycystic Kidney, Autosomal Dominant, Pregnancy, Signal Transduction, TRPP Cation Channels, Up-Regulation, beta Catenin
Show Abstract · Added August 12, 2010
Loss of polycystin-2 (PC2) in mice (Pkd2(-/-)) results in total body edema, focal hemorrhage, structural cardiac defects, abnormal left-right axis, hepatorenal and pancreatic cysts, and embryonic lethality. The molecular mechanisms by which loss of PC2 leads to these phenotypes remain unknown. We generated a model to allow targeted Pkd2 inactivation using the Cre-loxP system. Global inactivation of Pkd2 produced a phenotype identical to Pkd2(-/-) mice with undetectable PC2 protein and perinatal lethality. Using various Cre mouse lines, we found that kidney, pancreas, or time-specific deletion of Pkd2 led to cyst formation. In addition, we developed an immortalized renal collecting duct cell line with inactive Pkd2; these cells had aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis. They also significantly upregulated beta-catenin, axin2, and cMyc. Our results suggest that loss of PC2 disrupts normal behavior of renal epithelial cells through dysregulation of beta-catenin-dependent signaling, revealing a potential role for this signaling pathway in PC2-associated ADPKD.
1 Communities
1 Members
0 Resources
23 MeSH Terms
Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.
Dokmanovic-Chouinard M, Chung WK, Chevre JC, Watson E, Yonan J, Wiegand B, Bromberg Y, Wakae N, Wright CV, Overton J, Ghosh S, Sathe GM, Ammala CE, Brown KK, Ito R, LeDuc C, Solomon K, Fischer SG, Leibel RL
(2008) PLoS Genet 4: e1000137
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Blood Glucose, Chromosomes, Mammalian, Cloning, Molecular, Crosses, Genetic, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Glucose Tolerance Test, Haplotypes, Homozygote, Insulin, Male, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Obese, Molecular Sequence Data, Mutation, Protein Isoforms, Quantitative Trait Loci, Receptors, Cell Surface
Show Abstract · Added April 7, 2010
In 404 Lep(ob/ob) F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lep(ob). The phenotypes of B6.DBA congenic mice include reduced beta-cell replication rates accompanied by reduced beta-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated "Lisch-like" (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646-amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes.
1 Communities
1 Members
0 Resources
25 MeSH Terms
Control of thymocyte development and recombination-activating gene expression by the zinc finger protein Zfp608.
Zhang F, Thomas LR, Oltz EM, Aune TM
(2006) Nat Immunol 7: 1309-16
MeSH Terms: Animals, DNA-Binding Proteins, Flow Cytometry, Gene Expression, Genes, RAG-1, Immunoblotting, In Situ Hybridization, Lymphocytes, Mice, Mice, Congenic, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Thymus Gland, Zinc Fingers
Show Abstract · Added December 10, 2013
The products of recombination-activating gene 1 (Rag1) and Rag2 are required for T cell receptor gene assembly and thymocyte maturation, yet their transcriptional control mechanisms remain unclear. A congenic strain (called 'ZORI' here) with defects in Rag1 and Rag2 expression, thymocyte maturation and peripheral T cell homeostasis has been developed. Here, we mapped the mutation in this strain to a chromosome 18 locus containing a single known gene encoding the zinc finger protein Zfp608. This gene (Zfp608) was highly expressed in neonatal thymus but was extinguished thereafter. In contrast to wild-type mice, ZORI mice had sustained thymocyte expression of Zfp608 throughout life. The ZORI mutation produced a thymocyte-intrinsic developmental defect. Overexpression of Zfp608 in BALB/c thymocytes substantially impaired Rag1 and Rag2 expression, indicating the underlying mechanism for the defect in ZORI thymocyte development. Thus, the normal function of Zfp608 may be to prevent Rag1 and Rag2 expression in utero.
0 Communities
1 Members
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14 MeSH Terms
Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease.
Cantrell VA, Owens SE, Chandler RL, Airey DC, Bradley KM, Smith JR, Southard-Smith EM
(2004) Hum Mol Genet 13: 2289-301
MeSH Terms: Animals, Crosses, Genetic, DNA-Binding Proteins, Endothelins, Enteric Nervous System, Genes, Dominant, High Mobility Group Proteins, Hirschsprung Disease, Mice, Mice, Congenic, Mice, Inbred C3H, Mice, Inbred C57BL, Mutation, Pedigree, Receptor, Endothelin B, SOXE Transcription Factors, Severity of Illness Index, Signal Transduction, Transcription Factors
Show Abstract · Added March 20, 2014
Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric aganglionosis that are analogous to the variable aganglionosis seen in human HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of Sox10, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and Sox10 mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with aganglionosis.
1 Communities
2 Members
0 Resources
19 MeSH Terms
A murine locus on chromosome 18 controls NKT cell homeostasis and Th cell differentiation.
Zhang F, Liang Z, Matsuki N, Van Kaer L, Joyce S, Wakeland EK, Aune TM
(2003) J Immunol 171: 4613-20
MeSH Terms: Animals, Antigens, CD1, Antigens, CD1d, Cell Differentiation, Cells, Cultured, Chromosome Mapping, Crosses, Genetic, Genetic Carrier Screening, Genetic Linkage, Homeostasis, Immunophenotyping, Interleukin-4, Killer Cells, Natural, Lymphocyte Depletion, Mice, Mice, Congenic, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Quantitative Trait Loci, Spleen, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer, Th1 Cells, Th2 Cells
Show Abstract · Added December 10, 2013
Th cell differentiation is a critical event in the adaptive immune response. C57BL strains develop predominant Th1 responses while BALB/c develops a predominant Th2 response. To identify quantitative trait loci controlling this variation, we performed Th1/Th2 differentiation assays of F(1) x BALB/c progeny. A single strong quantitative trait locus was identified on chromosome 18, with weaker effects detectable on chromosomes 5, 12, and 14. By preparing a congenic BALB.B10.D2c18 strain, we were able to demonstrate that this single locus was sufficient to "repolarize" spleen cell cultures. This difference was not due to intrinsic differences in CD4(+) T cells. Rather, introgression of the chromosome 18 locus into BALB/c disrupted Va14Ja18 NKT cell homeostasis resulting in the almost complete absence of this T cell subset. Taken together, these data indicate that genes within chromosome 18 control strain-dependent development of Va14Ja18 NKT cells.
1 Communities
3 Members
0 Resources
26 MeSH Terms