title: Transcriptional and apoptotic responses of THP-1 cells to challenge with toxigenic, and non-toxigenic Bacillus anthracis.
abstract: BACKGROUND
  Bacillus anthracis secretes several virulence factors targeting different host organs and cell types during inhalational anthrax infection. The bacterial expression of a key virulence factor, lethal toxin (LeTx) is closely tied to another factor, edema toxin (EdTx). Both are transcribed on the same virulence plasmid (pXO1) and both have been the subject of much individual study. Their combined effect during virulent anthrax likely modulates both the global transcriptional and the phenotypic response of macrophages and phagocytes. In fact, responses brought about by the toxins may be different than each of their individual effects.
  
  
  RESULTS
  Here we report the transcriptional and apoptotic responses of the macrophage-like phagocytic cell line THP-1 exposed to B. anthracis Sterne (pXO1+) spores, and B. anthracis Delta Sterne (pXO1-) spores. These cells are resistant to LeTx-induced cytolysis, a phenotype seen in macrophages from several mouse strains which are sensitive to toxigenic anthrax infection. Our results indicate that the pXO1-containing strain induces higher pro-inflammatory transcriptional responses during the first 4 hours of interaction with bacterium, evident in the upregulation of several genes relevant to Nf-kappaB, phosphatases, prostaglandins, and TNF-alpha, along with decreases in expression levels of genes for mitochondrial components. Both bacterial strains induce apoptosis, but in the toxigenic strain-challenged cells, apoptosis is delayed.
  
  
  CONCLUSIONS
  This delay in apoptosis occurs despite the much higher level of TNF-alpha secretion induced by the toxigenic-strain challenge. Interestingly, CFLAR, an important apoptotic inhibitor which blocks apoptosis induced by large amounts of extracellular TNF-alpha, is upregulated significantly during toxigenic-strain infection, but not at all during non-toxigenic-strain infection, indicating that it may play a role in blocking or delaying TNF-alpha-mediated apoptosis. The suppression of apoptosis by the toxigenic anthrax strain is consistent with the notion that apoptosis itself may represent a protective host cell response.
authors.affiliation: Center for Bio/Molecular Science and Engineering Code 6900, US Naval Research Laboratory, Washington DC, USA. christopher.bradburne@cbmse.nrl.navy.mil
authors.forename: Christopher
authors.initials: C
authors.lastname: Bradburne
authors.forename: Myung-Chul
authors.initials: MC
authors.lastname: Chung
authors.forename: Qin
authors.initials: Q
authors.lastname: Zong
authors.forename: Karen
authors.initials: K
authors.lastname: Schlauch
authors.forename: Derong
authors.initials: D
authors.lastname: Liu
authors.forename: Taissia
authors.initials: T
authors.lastname: Popova
authors.forename: Anna
authors.initials: A
authors.lastname: Popova
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.forename: Dan
authors.initials: D
authors.lastname: Soppet
authors.forename: Serguei
authors.initials: S
authors.lastname: Popov
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology* / Q000382:microbiology; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis; D001408:Bacillus anthracis / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology* / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D037521:Virulence Factors / Q000276:immunology* / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; C030325:anthrax toxin