In Vivo Protective Role of Human Group IIA Phospholipase A2 against Experimental Anthrax

Abstract

Anthrax is an acute disease caused by Bacillus anthracis. Some animal species are relatively resistant to anthrax infection. This trait has been correlated to the extent of the local inflammatory reaction, suggesting innate immunity to be the first line of defense against B. anthracis infection in nonimmunized hosts. Group IIA secreted phospholipase A2 (sPLA2-IIA) is produced in particular by macrophages and possesses potent antibacterial activity especially against Gram-positive bacteria. We have previously shown in vitro that sPLA2-IIA kills both germinated B. anthracis spores and encapsulated bacilli. Here we show that sPLA2-IIA plays in vivo a protective role against experimental anthrax. Transgenic mice expressing human sPLA2-IIA are resistant to B. anthracis infection. In addition, in vivo administration of recombinant human sPLA2-IIA protects mice against B. anthracis infection. The protective effect was observed both with a highly virulent encapsulated nontoxinogenic strain and a wild-type encapsulated toxinogenic strain, showing that toxemia did not hinder the sPLA2-IIA-afforded protection. sPLA2-IIA, a natural component of the immune system, may thus be considered a novel therapeutic agent to be used in adjunct with current therapy for treating anthrax. Its anthracidal activity would be effective even against strains resistant to multiple antibiotics.

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA–Mediated Host Killing in the Airways

“…In a transgenic mouse model, sPLA2-IIA has been shown to protect animals from i.p. or pulmonary infections by S. aureus or Bacillus anthracis, respectively (17)(18)(19). However, these transgenic mice are artificial models with constitutive overexpression of sPLA2-IIA (36).…”

“…Thus, this enzyme represents a major actor in innate host defense against bacterial infections (12), in particular, by Gram-positive (G + ) bacteria that are highly susceptible to killing by sPLA2-IIA (13)(14)(15)(16). Previous studies showed that constitutively expressed human sPLA2-IIA protected transgenic mice from G + bacterial infections (16)(17)(18)(19).…”

Treatment of Experimental Anthrax with Recombinant Capsule Depolymerase

“…The availability of antibacterial enzymes for the treatment of anthrax, however, may prove valuable, particularly against antibiotic-resistant strains for which no treatment may be available. Recent reports indicate that such an approach can be used to treat experimental infections with B. anthracis using phospholipase A 2 (35) or Bacillus cereus using phage lysin (38) when enzyme is administered shortly after infection. CapD, while not directly bactericidal, facilitates host cell phagocytic killing of encapsulated bacilli, possibly by exposing pathogen-associated molecular patterns and promoting complement deposition on the bacterial surface.…”

A new era of secreted phospholipase A2

“…In addition to this substrate specifi city, the highly cationic nature of sPLA 2 -IIA, which is not shared with other sPLA 2 s, is essential for bacterial membrane hydrolysis by this enzyme ( 51,52 ). As such, PLA2G2A -transgenic mice, or wild-type mice treated with recombinant sPLA 2 -IIA, are resistant to pneumonia and sepsis following bacterial infection ( 31,32,(53)(54)(55). For this reason, sPLA 2 -IIA can be regarded as a "bactericidal sPLA 2 ."…”