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Effect of Bacillus anthracis virulence factors on human dendritic cell activation.

ABSTRACT: Bacillus anthracis possesses three primary virulence factors: capsule, lethal toxin (LT), and edema toxin (ET). Dendritic cells (DCs) are critical to innate and acquired immunity and represent potential targets for these factors. We examined the ability of B. anthracis spores and bacilli to stimulate human monocyte-derived DC (MDDC), primary myeloid DC (mDC), and plasmacytoid DC (pDC) cytokine secretion. Exposure of MDDCs and mDCs to spores or vegetative bacilli of the genetically complete strain UT500 induced significantly increased cytokine secretion. Spores lacking genes required for capsule biosynthesis stimulated significantly higher cytokine secretion than UT500 spores from mDCs, but not MDDCs. In contrast, bacilli lacking capsule stimulated significantly higher cytokine secretion than UT500 bacilli in both MDDCs and mDCs. Spores or bacilli lacking both LT and ET stimulated significantly higher cytokine secretion than UT500 spores or bacilli, respectively, in both mDCs and MDDCs. pDCs exposed to spores or bacilli did not produce significant amounts of cytokines even when virulence factors were absent. In conclusion, B. anthracis employs toxins as well as capsule to inhibit human MDDC and mDC cytokine secretion, whereas human pDCs respond poorly even when capsule or both toxins are absent.

SUBMITTER: Hahn AC

PROVIDER: S-EPMC2664623 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Effect of Bacillus anthracis virulence factors on human dendritic cell activation.

Hahn Andrew C AC Lyons C Rick CR Lipscomb Mary F MF

Human immunology 20080726 9

Bacillus anthracis possesses three primary virulence factors: capsule, lethal toxin (LT), and edema toxin (ET). Dendritic cells (DCs) are critical to innate and acquired immunity and represent potential targets for these factors. We examined the ability of B. anthracis spores and bacilli to stimulate human monocyte-derived DC (MDDC), primary myeloid DC (mDC), and plasmacytoid DC (pDC) cytokine secretion. Exposure of MDDCs and mDCs to spores or vegetative bacilli of the genetically complete strai ...[more]

PMID: 18662733

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Project description:Emerging B. cereus strains that cause anthrax-like disease have been isolated in Cameroon (CA strain) and Côte d'Ivoire (CI strain). These strains are unusual, because their genomic characterisation shows that they belong to the B. cereus species, although they harbour two plasmids, pBCXO1 and pBCXO2, that are highly similar to the pXO1 and pXO2 plasmids of B. anthracis that encode the toxins and the polyglutamate capsule respectively. The virulence factors implicated in the pathogenicity of these B. cereus bv anthracis strains remain to be characterised. We tested their virulence by cutaneous and intranasal delivery in mice and guinea pigs; they were as virulent as wild-type B. anthracis. Unlike as described for pXO2-cured B. anthracis, the CA strain cured of the pBCXO2 plasmid was still highly virulent, showing the existence of other virulence factors. Indeed, these strains concomitantly expressed a hyaluronic acid (HA) capsule and the B. anthracis polyglutamate (PDGA) capsule. The HA capsule was encoded by the hasACB operon on pBCXO1, and its expression was regulated by the global transcription regulator AtxA, which controls anthrax toxins and PDGA capsule in B. anthracis. Thus, the HA and PDGA capsules and toxins were co-regulated by AtxA. We explored the respective effect of the virulence factors on colonisation and dissemination of CA within its host by constructing bioluminescent mutants. Expression of the HA capsule by itself led to local multiplication and, during intranasal infection, to local dissemination to the adjacent brain tissue. Co-expression of either toxins or PDGA capsule with HA capsule enabled systemic dissemination, thus providing a clear evolutionary advantage. Protection against infection by B. cereus bv anthracis required the same vaccination formulation as that used against B. anthracis. Thus, these strains, at the frontier between B. anthracis and B. cereus, provide insight into how the monomorphic B. anthracis may have emerged.

Project description:AtxA, the master virulence regulator of Bacillus anthracis, regulates the expression of three toxins and genes for capsule formation that are required for the pathogenicity of B. anthracis. Recent transcriptome analyses showed that AtxA affects a large number of genes on the chromosome and plasmids, suggesting a role as a global regulator. However, information on genes directly regulated by AtxA is scarce. In this work, we conducted genome-wide analyses and cataloged the binding sites of AtxA in vivo and transcription start sites on the B. anthracis genome. By integrating these results, we detected eight genes as direct regulons of AtxA. These consisted of five protein-coding genes, including two of the three toxin genes, and three genes encoding the small RNAs XrrA and XrrB and a newly discovered 95-nucleotide small RNA, XrrC. Transcriptomes from single-knockout mutants of these small RNAs revealed changes in the transcription levels of genes related to the aerobic electron transport chain, heme biosynthesis, and amino acid metabolism, suggesting their function for the control of cell physiology. These results reveal the first layer of the gene regulatory network for the pathogenicity of B. anthracis and provide a data set for the further study of the genomics and genetics of B. anthracis. IMPORTANCE Bacillus anthracis is the Gram-positive bacterial species that causes anthrax. Anthrax is still prevalent in countries mainly in Asia and Africa, where it causes economic damage and remains a public health issue. The mechanism of pathogenicity is mainly explained by the three toxin proteins expressed from the pXO1 plasmid and by proteins involved in capsule formation expressed from the pXO2 plasmid. AtxA is a protein expressed from the pXO1 plasmid that is known to upregulate genes involved in toxin production and capsule formation and is thus considered the master virulence regulator of B. anthracis. Therefore, understanding the detailed mechanism of gene regulation is important for the control of anthrax. The significance of this work lies in the identification of genes that are directly regulated by AtxA via genome-wide analyses. The results reveal the first layer of the gene regulatory network for the pathogenicity of B. anthracis and provide useful resources for a further understanding of B. anthracis.

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Effect of Bacillus anthracis virulence factors on human dendritic cell activation.

Publications

Effect of Bacillus anthracis virulence factors on human dendritic cell activation.

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