Edema Toxin Impairs Anthracidal Phospholipase A2 Expression by Alveolar Macrophages

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Abstract
Bacillus anthracis, the etiological agent of anthrax, is a spore-forming Gram-positive bacterium. Infection with this pathogen results in multisystem dysfunction and death. The pathogenicity of B. anthracis is due to the production of virulence factors, including edema toxin (ET). Recently, we established the protective role of type-IIA secreted phospholipase A2 (sPLA2-IIA) against B. anthracis. A component of innate immunity produced by alveolar macrophages (AMs), sPLA2-IIA is found in human and animal bronchoalveolar lavages at sufficient levels to kill B. anthracis. However, pulmonary anthrax is almost always fatal, suggesting the potential impairment of sPLA2-IIA synthesis and/or action by B. anthracis factors. We investigated the effect of purified ET and ET-deficient B. anthracis strains on sPLA2-IIA expression in primary guinea pig AMs. We report that ET inhibits sPLA2-IIA expression in AMs at the transcriptional level via a cAMP/protein kinase A–dependent process. Moreover, we show that live B. anthracis strains expressing functional ET inhibit sPLA2-IIA expression, whereas ET-deficient strains induced this expression. This stimulatory effect, mediated partly by the cell wall peptidoglycan, can be counterbalanced by ET. We conclude that B. anthracis down-regulates sPLA2-IIA expression in AMs through a process involving ET. Our study, therefore, describes a new molecular mechanism implemented by B. anthracis to escape innate host defense. These pioneering data will provide new molecular targets for future intervention against this deathly pathogen. All mammals are susceptible to infection by Bacillus anthracis, the etiological agent of anthrax. Infection can occur either accidentally or as a potential consequence of a terrorism threat. Pulmonary infection is the most life-threatening form of the disease, causing a near 100% mortality. Despite appropriate therapy, all forms of infection may progress to fatal systemic anthrax, characterized by sepsis and respiratory failure. Thus, it is important to understand the mechanisms of host defense against B. anthracis. We have previously shown that alveolar macrophages produce an enzyme involved in innate defense that can kill B. anthracis: the enzyme is known as secreted phospholipase A2-IIA (sPLA2-IIA). The alveolar macrophage is one of the first cell types to come in contact with B. anthracis. In this study, we show that live B. anthracis spores stimulate the synthesis of sPLA2-IIA, this stimulation being counterbalanced by the inhibitory effect of the edema toxin produced by germinated spores and bacilli. Our study suggests that inhibition of sPLA2-IIA synthesis by edema toxin is a mechanism by which B. anthracis can escape innate host defense. These pioneering data provide new molecular targets for future intervention against this deadly pathogen.