title: Differential contribution of Bacillus anthracis toxins to pathogenicity in two animal models.
abstract: The virulence of Bacillus anthracis, the causative agent of anthrax, stems from its antiphagocytic capsule, encoded by pXO2, and the tripartite toxins encoded by pXO1. The accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play major roles in pathogenicity. We tested this assumption by a systematic study of mutants with combined deletions of the pag, lef, and cya genes, encoding protective antigen (PA), lethal factor (LF), and edema factor (EF), respectively. The resulting seven mutants (single, double, and triple) were evaluated following subcutaneous (s.c.) and intranasal (i.n.) inoculation in rabbits and guinea pigs. In the rabbit model, virulence is completely dependent on the presence of PA. Any mutant bearing a pag deletion behaved like a pXO1-cured mutant, exhibiting complete loss of virulence with attenuation indices of over 2,500,000 or 1,250 in the s.c. or i.n. route of infection, respectively. In marked contrast, in guinea pigs, deletion of pag or even of all three toxin components resulted in relatively moderate attenuation, whereas the pXO1-cured bacteria showed complete attenuation. The results indicate that a pXO1-encoded factor(s), other than the toxins, has a major contribution to the virulence mechanism of B. anthracis in the guinea pig model. These unexpected toxin-dependent and toxin-independent manifestations of pathogenicity in different animal models emphasize the importance and need for a comprehensive evaluation of B. anthracis virulence in general and in particular for the design of relevant next-generation anthrax vaccines.
authors.affiliation: Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel. haiml@iibr.gov.il
authors.forename: Haim
authors.initials: H
authors.lastname: Levy
authors.forename: Shay
authors.initials: S
authors.lastname: Weiss
authors.forename: Zeev
authors.initials: Z
authors.lastname: Altboum
authors.forename: Josef
authors.initials: J
authors.lastname: Schlomovitz
authors.forename: Itai
authors.initials: I
authors.lastname: Glinert
authors.forename: Assa
authors.initials: A
authors.lastname: Sittner
authors.forename: Avigdor
authors.initials: A
authors.lastname: Shafferman
authors.forename: David
authors.initials: D
authors.lastname: Kobiler
mesh_terms: D000818:Animals; D000881:Anthrax / Q000382:microbiology*; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D001408:Bacillus anthracis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D004269:DNA, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D005838:Genotype; D006168:Guinea Pigs; D016133:Polymerase Chain Reaction; D011817:Rabbits; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004269:DNA, Bacterial; C030325:anthrax toxin