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Salmonella typhimurium causes enteric and systemic disease by invading the intestinal epithelium of the distal ileum, a process requiring the invasion genes of Salmonella pathogenicity island 1 (SPI-1). BarA, a sensor kinase postulated to interact with the response regulator SirA, is required for the expression of SPI-1 invasion genes. We found, however, that a barA null mutation had little effect on virulence using the mouse model for septicaemia. This confounding result led us to seek environmental signals present in the distal ileum that might supplant the need for BarA. We found that acetate restored the expression of invasion genes in the barA mutant, but had no effect on a sirA mutant. Acetate had its effect only at a pH that allowed its accumulation within the bacterial cytoplasm and not with the deletion of ackA and pta, the two genes required to produce acetyl-phosphate. These results suggest that the rising concentration of acetate in the distal ileum provides a signal for invasion gene expression by the production of acetyl-phosphate in the bacterial cytoplasm, a pathway that bypasses barA. We also found that a Delta(ackA-pta) mutation alone had no effect on virulence but, in combination with Delta(barA), it increased the oral LD50 24-fold. Thus, the combined loss of the BarA- and acetate-dependent pathways is required to reduce virulence. Two other short-chain fatty acids (SCFA), propionate and butyrate, present in high concentrations in the caecum and colon, had effects opposite to those of acetate: neither restored invasion gene expression in the barA mutant, and both, in fact, reduced expression in the wild-type strain. Further, a combination of SCFAs found in the distal ileum restored invasion gene expression in the barA mutant, whereas colonic conditions failed to do so and also reduced expression in the wild-type strain. These results suggest that the concentration and composition of SCFAs in the distal ileum provide a signal for productive infection by Salmonella, whereas those of the large intestine inhibit invasion.
Mol Microbiol 2002 Dec
PMID:Intestinal short-chain fatty acids alter Salmonella typhimurium invasion gene expression and virulence through BarA/SirA. 1245 29

Neuroblastic tumors are a broad biological and clinical spectrum of neoplastic disease that has long captured the attention of clinicians and scientists alike. It is the most common solid extracranial tumor in children and accounts for 8-10% of all childhood tumors. Tumors are derived from neural crest cells and neural differentiation is common. Neuroblastoma is unique in that it presents with at least three distinct patterns of disease. Locoregional disease (Stage 1, 2, 3) does not metastasize to bone or bone marrow. Stage 4 is a systemic disease with widespread metastasis that responds to chemotherapy but many develop resistance. Stage 4s presents in infancy, is widespread and can spontaneously regress with no intervention, leaving a focus of fibrosis or calcification. Prognosis correlates with age, stage and tumor biological profile. The goal of this review is to provide an overview of the disease and highlight diagnostic, prognostic and therapeutic advances in neuroblastoma. Recommendations and resources for the evaluation and treatment of this disease are outlined.
Expert Rev Mol Diagn 2003 Jan
PMID:Genomic medicine and neuroblastoma. 1252 63

Salmonella must express and deploy a type III secretion system located in Salmonella pathogenicity island 2 (SPI-2) in order to survive in host phagocytic vacuoles and to cause systemic infection in mouse models of typhoid fever. A genome-wide approach to screening for Salmonella genes that are transcriptionally co-regulated in vitro with SPI-2 genes was used to identify bacterial loci that might function in a mouse model of systemic disease. Strains with mutations in three SPI-2 co-expressed genes were constructed and tested for their ability to cause disease in mice. We found that virK, a homologue of a Shigella virulence determinant, and rcsC, a sensor kinase, are important at late stages of infection. A second Salmonella gene that has VirK homology, somA, is also important for systemic infection in mice. We have shown that expression of both virK and somA requires the transcription factor PhoP, whereas rcsC does not. Additionally, rcsC expression does not require the transcription factor OmpR, but expression of one of the known targets of RcsC, the yojN rcsB putative operon, does require OmpR. virK, somA and rcsC are expressed in tissue culture macrophages and confer Salmonella resistance to the cationic peptide polymyxin B. We conclude that virK, somA and rcsC are important for late stages of Salmonella enteric fever, and that they probably contribute to the remodelling of the bacterial outer membrane in response to the host environment.
Mol Microbiol 2003 Apr
PMID:virK, somA and rcsC are important for systemic Salmonella enterica serovar Typhimurium infection and cationic peptide resistance. 1267 99

Salmonella infections continue to cause gastrointestinal and systemic disease throughout the world. Another concern with this pathogen is the ability to acquire integrons that confer resistance to multiple antibiotics. For multiresistant Salmonella enterica serotype Typhimurium, the most common multiresistant Salmonella serotype, an integron structure can be found between thdF and a retron. Our objective was to investigate the utility of a 450 bp thdF-retron amplicon as an indicator of an insertless thdF-retron junction thus indicating an integron-free strain. Surprisingly, we found that the 450 bp thdF-retron amplicon was present, and thus incorrectly suggesting an integron-free status, in some multiresistant S. enterica serotype Typhimurium isolates. However, this phenomenon was not observed if the isolate was enriched in the presence of two antibiotics. This demonstrates that, within some individual clinical isolates of multiresistant S. enterica serotype Typhimurium, there exists a small subpopulation of integron-free bacteria. Consequently, it appears that the thdF-retron amplicon is an inaccurate predictor of integron status in S. enterica serotype Typhimurium unless multiresistance is used as a selection tool during enrichment.
Mol Cell Probes 2003 Aug
PMID:Avoidance of false PCR results with the integron-retron junction in multiple antibiotic resistant Salmonella enterica serotype Typhimurium. 1294 21

The highly conserved fungal Ste12 transcription factor family of proteins play critical roles in the regulation of many cellular processes including mating, cell wall biosynthesis, filamentation and invasive growth. They are also important mediators of fungal virulence. The Candida glabrata STE12 homologue was cloned. The encoded protein has a single DNA binding homeodomain but lacks both a C2H2 zinc finger DNA binding domain and an apparent Dig1/Dig2 regulatory motif. Candida glabrata STE12 can functionally complement the nitrogen starvation induced filamentation and mating defects of Saccharomyces cerevisiae ste12 mutants. We also show that C. glabrata STE12 is required for nitrogen starvation-induced filamentation as ste12 mutants rarely produce pseudohyphae on nitrogen depleted media. Finally we describe a novel murine model of C. glabrata systemic disease and use this to demonstrate that C. glabrata ste12 mutants, although still able to cause disease, are attenuated for virulence compared with STE12 reconstituted strains. Candida glabrata STE12 is therefore the first virulence factor encoding gene to be described in this increasingly important fungal pathogen.
Mol Microbiol 2003 Nov
PMID:Candida glabrata STE12 is required for wild-type levels of virulence and nitrogen starvation induced filamentation. 1462 17

Histoplasma capsulatum is a fungal pathogen that causes respiratory and systemic disease by proliferating within macrophages. While much is known about histoplasmosis, only a single virulence factor has been defined, in part because of the inefficiency of Histoplasma reverse genetics. As an alternative to allelic replacement, we have developed a telomeric plasmid-based system for silencing gene expression in Histoplasma by RNA interference (RNAi). Episomal expression of long RNAs that form stem-loop structures triggered gene silencing. To test the effectiveness of RNAi in Histoplasma, we depleted expression of a gfp transgene as well as two endogenous genes, ADE2 and URA5, and showed significant reductions in corresponding gene function. Silencing was target gene specific, stable during macrophage infection and reversible. We used RNAi targeting AGS1 (encoding alpha-(1,3)-glucan synthase) to deplete levels of alpha-(1,3)-glucan, a cell wall polysaccharide. Loss of alpha-(1,3)-glucan by RNAi yielded phenotypes indistinguishable from an AGS1 deletion: attenuation of the ability to kill macrophages and colonize murine lungs. This demonstrates for the first time that alpha-(1,3)-glucan is an important contributor to Histoplasma virulence.
Mol Microbiol 2004 Jul
PMID:RNA interference in Histoplasma capsulatum demonstrates a role for alpha-(1,3)-glucan in virulence. 1522 11

This chapter describes the major principals, methods, and immunization protocols for the induction of a systemic autoimmune arthritis in genetically susceptible murine strains. The model is called proteoglycan-induced arthritis (PGIA) because the antigenic/arthritogenic material is isolated from cartilage. This autoimmune systemic disease is induced by intraperitoneal immunization of either BALB/c or certain C3H colonies with cartilage proteoglycan, an abundant component in articular cartilage. The chapter presents (a) methodological details on how to purify cartilage proteoglycan aggrecan by cesium chloride gradient centrifugation; (b) substitution of this highly purified antigenic/arthritogenic material with a crude cartilage extract obtained from knee joint cartilages removed during joint replacement surgery; and (c) substitution of human cartilage proteoglycan with pig, dog, sheep, or bovine cartilage proteoglycans for arthritis induction. The cartilage proteoglycan aggrecan requires partial deglycosylation, and necessary materials, methods, and protocols are described. In addition, basic methods for measuring antigen-specific T-cell-dependent immune responses, antibody production, serum cytokine levels, and alternative solutions for adoptive transfers are also described.
Methods Mol Med 2004
PMID:Proteoglycan aggrecan-induced arthritis: a murine autoimmune model of rheumatoid arthritis. 1528 93

Thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are the two key enzymes in mitochondrial DNA (mtDNA) precursor synthesis. Deficiencies in TK2 or dGK activity, due to genetic alteration, have been shown to cause tissue-specific depletion of mtDNA. In the case of TK2 deficiency, affected individuals suffer severe myopathy and, in the case of dGK deficiency, devastating liver or multi-systemic disease. Here, we report clinical and biochemical findings from two patients with mtDNA depletion syndrome. Patient A was a compound heterozygote carrying the previously reported T77M mutation and a novel mutation (R161K) in the TK2 gene. Patient B carried a novel mutation (L250S) in the dGK gene. The clinical symptoms of patient A included muscular weakness and exercise intolerance due to a severe mitochondrial myopathy associated with a 92% reduction in mtDNA. There was minimal involvement of other organs. Patient B suffered from rapidly progressive, early onset fatal liver failure associated with profoundly decreased mtDNA levels in liver and, to a lesser extent, in skeletal muscle. Site-directed mutagenesis was used to introduce the mutations detected in patients A and B into the TK2 and dGK cDNAs, respectively. We then characterized each of these recombinant enzymes. Catalytic activities of the three mutant enzymes were reduced to about 2-4% for TK2 and 0.5% for dGK as compared to the wild-type enzymes. Altered competition between dCyd and dThd was observed for the T77M mutant. The residual activities of the two mitochondrial enzymes correlated directly with disease development.
Mol Genet Metab 2005 Jan
PMID:Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. 1563 97

Salmonella enterica serovar Typhimurium (S. typhimurium) infects a wide variety of mammalian hosts and in rodents causes a typhoid-like systemic disease involving replication of bacteria inside macrophages within reticuloendothelial tissues. Previous studies demonstrated that the mig-14 and virK genes of Salmonella enterica are important in bacterial resistance to anti-microbial peptides and are necessary for continued replication of S. typhimurium in the liver and spleen of susceptible mice after orogastric inoculation. In this work we report that inflammatory signalling via interferon-gamma (IFN-gamma) is crucial to controlling replication of mig-14 mutant bacteria within the liver and spleen of mice after oral infection. Using a Salmonella persistence model recently developed in our laboratory, we further demonstrate that mig-14 contributes to long-term persistence of Salmonella in the spleen and mesenteric lymph nodes of chronically infected mice. Both mig-14 and virK contribute to the survival of Salmonella in macrophages treated with IFN-gamma and are necessary for resistance to cathelin-related anti-microbial peptide (CRAMP), an anti-microbial peptide expressed at high levels in activated mouse macrophages. We also show that both Mig-14 and VirK inhibit the binding of CRAMP to Salmonella, and demonstrate that Mig-14 is an inner membrane-associated protein. We further demonstrate by transmission electron microscopy that the primary locus of CRAMP activity appears to be intracytoplasmic, rather than at the outer membrane, suggesting that Mig-14 may prevent the penetration of the inner membrane by CRAMP. Together, these data indicate an important role for mig-14 in anti-microbial peptide resistance in vivo, and show that this resistance is important to the survival of Salmonella in systemic sites during both acute and persistent infection.
Mol Microbiol 2005 Feb
PMID:Mig-14 is an inner membrane-associated protein that promotes Salmonella typhimurium resistance to CRAMP, survival within activated macrophages and persistent infection. 1566 Oct 16

Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue, affecting mainly skin, eye and the cardiovascular system. PXE is characterized by dystrophic mineralization of elastic fibres. The condition is caused by loss of function mutations in ABCC6. We generated Abcc6 deficient mice (Abcc6-/-) by conventional gene targeting. As shown by light and electron microscopy Abcc6-/- mice spontaneously developed calcification of elastic fibres in blood vessel walls and in Bruch's membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Newly developed monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6-/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. We conclude that the phenotype of the Abcc6-/- mouse shares calcification of elastic fibres with human PXE pathology, which makes this model a useful tool to further investigate the aetiology of PXE. Our data support the hypothesis that PXE is in fact a systemic disease.
Hum Mol Genet 2005 Jul 01
PMID:Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum. 1588 84


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