Monoclonal antibody against the poly-γ-d-glutamic acid capsule of Bacillus anthracis protects mice from enhanced lethal toxin activity due to capsule and anthrax spore challenge

• Published in: Biochimica et biophysica acta Vol. 1830; no. 3; pp. 2804 - 2812
• Main Authors: Jang, Jeyoun, Cho, Minhui, Lee, Hae-Ri, Cha, Kiweon, Chun, Jeong-Hoon, Hong, Kee-Jong, Park, Jungchan, Rhie, Gi-eun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2013
• Subjects: Animals; anthrax; Anthrax - immunology; Anthrax - microbiology; Anthrax - mortality; Anthrax - prevention & control; Anthrax Vaccines - administration & dosage; Antibodies, Bacterial - administration & dosage; Antibodies, Bacterial - biosynthesis; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - biosynthesis; antigens; Antigens, Bacterial - immunology; Bacillus anthracis; Bacillus anthracis - drug effects; Bacillus anthracis - immunology; Bacillus anthracis - pathogenicity; bacteria; Bacterial Capsules - immunology; Bacterial Toxins - immunology; blood; Cells, Cultured; cognition; complement; cytotoxicity; encapsulation; Female; Humans; immunization; Immunization, Passive; Kinetics; Lethal toxin; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred BALB C; Modeling; Molecular Docking Simulation; monitoring; monoclonal antibodies; Monoclonal antibody; pathogenesis; Poly-γ-d-glutamic acid capsule; Polyglutamic Acid - analogs & derivatives; Polyglutamic Acid - antagonists & inhibitors; Polyglutamic Acid - immunology; spores; Spores, Bacterial - drug effects; Spores, Bacterial - immunology; Spores, Bacterial - pathogenicity; Survival Analysis; virulence; Virulence Factors - antagonists & inhibitors; Virulence Factors - immunology; EF; Bacillus anthracis; Poly-γ-d-glutamic acid capsule; HRP; MAPKK; LT; i.p; Lethal toxin; PGA; Monoclonal antibody; MAPK; Modeling; mAb; PA; 3D; LF
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.11.006

The poly-γ-d-glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis, protects bacilli from immune surveillance and allows its unimpeded growth in the host. Recently, the importance of the PGA in the pathogenesis of anthrax infection has been reported. The PGA capsule is associated with lethal toxin (LT) in the blood of experimentally infected animals and enhances the cytotoxicity of LT. To investigate the role of anti-PGA Abs on progression of anthrax infection, two mouse anti-PGA mAbs with Kd values of 0.8μM and 2.6μM respectively were produced and in silico three dimensional (3D) models of mAbs with their cognitive PGA antigen complex were analyzed. Anti-PGA mAbs specifically bound encapsulated B. anthracis H9401 and showed opsonophagocytosis activity against the bacteria with complement. The enhancement effect of PGA on LT-mediated cytotoxicity was confirmed ex vivo using mouse bone marrow-derived macrophages and was effectively inhibited by anti-PGA mAb. Passive immunization of mAb completely protected mice from PGA-enhanced LT toxicity and partially rescued mice from anthrax spore challenges. 3D structure models of these mAbs and PGA complex support specific interactions between CDR and cognitive PGA. These results indicate that mouse mAb against PGA capsule prevents the progress of anthrax disease not only by eliminating the vegetative form of encapsulated B. anthracis but also by inhibiting the enhanced cytotoxic activity of LT by PGA through specific binding with PGA capsule antigen. Our results suggest a potential role for PGA antibodies in preventing and treating anthrax infection. ► We characterized two new mouse anti-poly-γ-d-glutamic acid (PGA) antibodies. ► In silico three dimensional models of mAbs with PGA complex were analyzed. ► The enhancement of PGA on LT-mediated cytotoxicity was inhibited by anti-PGA mAb. ► mAb partially rescued mice from anthrax spore challenge through opsonophagocytosis. ► Data supports the role of anti-PGA antibody in prevention and treatment of anthrax.