Treatment of experimental anthrax with recombinant capsule depolymerase.
Bacillus anthracis produces an antiphagocytic gamma-linked poly-D-glutamic acid capsule that is required for virulence. Capsule depolymerase (CapD) is a membrane-associated poly-gamma-glutamate-specific depolymerase encoded on the B. anthracis capsule plasmid, pX02, that is reported to contribute to virulence by anchoring the capsule to the peptidoglycan and partially degrading high-molecular-weight capsule from the bacterial surface. We previously demonstrated that treatment with CapD effectively removes the capsule from anthrax bacilli, rendering them susceptible to phagocytic killing in vitro. Here we report that CapD promoted in vivo phagocytic killing of B. anthracis bacilli by mouse peritoneal neutrophils and that parenteral administration of CapD protected mice in two models of anthrax infection. CapD conferred significant protection compared with controls when coinjected with encapsulated bacilli from fully virulent B. anthracis Ames or the nontoxigenic encapsulated strain Delta Ames and when injected 10 min after infection with encapsulated bacilli from B. anthracis Ames. Protection was also observed when CapD was administered 30 h after infection with B. anthracis Delta Ames spores, while significant protection could not be demonstrated following challenge with B. anthracis Ames spores. These data support the proposed role of capsule in B. anthracis virulence and suggest that strategies to target anthrax bacilli for neutrophil killing may lead to novel postexposure therapies.
Scorpio
Angelo
A
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA. angelo.scorpio@amedd.army.mil
Tobery
Steven A
SA
Ribot
Wilson J
WJ
Friedlander
Arthur M
AM
D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000382:microbiology; D001408:Bacillus anthracis / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D016667:Bacterial Capsules / Q000378:metabolism*; D005260:Female; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D013171:Spores, Bacterial / Q000502:physiology; D016896:Treatment Outcome; D014774:Virulence
D011994:Recombinant Proteins; D006026:Glycoside Hydrolases; C022562:capsular-polysaccharide galactohydrolase