The Role of the spv Genes in Salmonella Pathogenesis

Salmonella strains cause three main types of diseases in people: gastroenteritis, enteric (typhoid) fever, and non-typhoid extra-intestinal disease with bacteremia. Genetic analysis indicates that each clinical syndrome requires distinct sets of virulence genes, and Salmonella isolates differ in their constellation of virulence traits. The spv locus is strongly associated with strains that cause non-typhoid bacteremia, but are not present in typhoid strains. The spv region contains three genes required for the virulence phenotype in mice: the positive transcriptional regulator spvR and two structural genes spvB and spvC. SpvB and SpvC are translocated into the host cell by the Salmonella pathogenicity island-2 type-three secretion system. SpvB prevents actin polymerization by ADP-ribosylation of actin monomers, while SpvC has phosphothreonine lyase activity and has been shown to inhibit MAP kinase signaling. The exact mechanisms by which SpvB and SpvC act in concert to enhance virulence are still unclear. SpvB exhibits a cytotoxic effect on host cells and is required for delayed cell death by apoptosis following intracellular infection. Strains isolated from systemic infections of immune compromised patients, particularly HIV patients, usually carry the spv locus, strongly suggesting that CD4 T cells are required to control disease due to Salmonella that are spv positive. This association is not seen with typhoid fever, indicating that the pathogenesis and immunology of typhoid have fundamental differences from the syndrome of non-typhoid bacteremia

Biology and Clinical Significance of Virulence Plasmids in Salmonella Serovars

Non-typhoid Salmonella strains containing virulence plasmids are highly associated with bacteremia and disseminated infection in humans. These plasmids are found in Salmonella serovars adapted to domestic animals, such as Salmonella dublin and Salmonella choleraesuis, as well as in the widely distributed pathogens Salmonella typhimurium and Salmonella enteritidis. Although virulence plasmids differ between serovars, all contain a highly conserved 8-kb region containing the spv locus that encodes the spvR regulatory gene and four structural spvABCD genes. Studies in mice suggest that the spv genes enhance the ability of Salmonella strains to grow within cells of the reticuloendothelial system. The spv genes are not expressed during exponential growth in vitro but are rapidly induced following entry of Salmonella strains into mammalian cells, including macrophages. Transcription of the spv genes is controlled by the stationary-phase (T factor RpoS, and mutations in RpoS abolish virulence. These studies suggest that the ability of Salmonella strains to respond to starvation stress in the host tissues is an essential component of virulenc

RETRACTED: Induction of a Homeostatic Circuit in Lung Tissue by Microbial Compounds

This article has been retracted at the request of the inhouse Editor, Peter Lee, and the authors. The text below has been agreed between Peter Lee and the corresponding author. Please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).Reason: The authors discovered that a duplication of several gel images occurred during the preparation of the above manuscript. Specifically, the gel images in Figure 2A were duplicated within Figure 2A, and in Figures 5F and 6B. These figures are important in showing the amount of Smad 2/3 as an indicator of alveolar macrophage-epithelial cell interactions, which explains the mechanism of the proposed homeostatic circuit in the lungs, and thus we are retracting the manuscript. The authors stand by the validity of the other figures, and sincerely apologize for the inconvenience caused by this retraction

Anthrax Toxins Inhibit Neutrophil Signaling Pathways in Brain Endothelium and Contribute to the Pathogenesis of Meningitis

Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood.Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Gro alpha) and CXCL2 (Gro beta), thereby strongly contrasting hBMEC responses observed with other meningeal pathogens. Further studies using specific anthrax toxin-mutants, quantitative RT-PCR, ELISA and in vivo assays indicated that anthrax toxins actively suppress chemokine production and neutrophil recruitment during infection, allowing unrestricted proliferation and dissemination of the bacteria. Finally, mice challenged with B. anthracis Sterne, but not the toxin-deficient strain, developed meningitis.These results suggest a significant role for anthrax toxins in thwarting the BBB innate defense response promoting penetration of bacteria into the central nervous system. Furthermore, establishment of a mouse model for anthrax meningitis will aid in our understanding of disease pathogenesis and development of more effective treatment strategies

Complement C3d Conjugation to Anthrax Protective Antigen Promotes a Rapid, Sustained, and Protective Antibody Response

B. anthracis is the causative agent of anthrax. Pathogenesis is primarily mediated through the exotoxins lethal factor and edema factor, which bind protective antigen (PA) to gain entry into the host cell. The current anthrax vaccine (AVA, Biothrax™) consists of aluminum-adsorbed cell-free filtrates of unencapsulated B. anthracis, wherein PA is thought to be the principle target of neutralization. In this study, we evaluated the efficacy of the natural adjuvant, C3d, versus alum in eliciting an anti-PA humoral response and found that C3d conjugation to PA and emulsion in incomplete Freund's adjuvant (IFA) imparted superior protection from anthrax challenge relative to PA in IFA or PA adsorbed to alum. Relative to alum-PA, immunization of mice with C3d-PA/IFA augmented both the onset and sustained production of PA-specific antibodies, including neutralizing antibodies to the receptor-binding portion (domain 4) of PA. C3d-PA/IFA was efficacious when administered either i.p. or s.c., and in adolescent mice lacking a fully mature B cell compartment. Induction of PA-specific antibodies by C3d-PA/IFA correlated with increased efficiency of germinal center formation and plasma cell generation. Importantly, C3d-PA immunization effectively protected mice from intranasal challenge with B. anthracis spores, and was approximately 10-fold more effective than alum-PA immunization or PA/IFA based on dose challenge. These data suggest that incorporation of C3d as an adjuvant may overcome shortcomings of the currently licensed aluminum-based vaccine, and may confer protection in the early days following acute anthrax exposure