Abstract
Bacillus anthracis, the causative agent of anthrax, has been a focus of study in host-pathogen dynamics since the nineteenth century. While the interaction between anthrax and host macrophages has been extensively modeled, comparatively little is known about the effect of anthrax on the immune function of neutrophils, a key frontline effector of innate immune defense. Here we showed that depletion of neutrophils significantly enhanced mortality in a systemic model of anthrax infection in mice. Ex vivo, we found that freshly isolated human neutrophils can rapidly kill anthrax, with specific inhibitor studies showing that phagocytosis and reactive oxygen species (ROS) generation contribute to this efficient bacterial clearance. Anthrax toxins, comprising lethal toxin (LT) and edema toxin (ET), are known to have major roles in B. anthracis macrophage resistance and systemic toxicity. Employing isogenic wild-type and mutant toxin-deficient B. anthracis strains, we show that despite previous studies that reported inhibition of neutrophil function by purified LT or ET, endogenous production of these toxins by live vegetative B. anthracis failed to alter key neutrophil functions. The lack of alteration in neutrophil function is accompanied by rapid killing of B. anthracis by neutrophils, regardless of the bacteria's expression of anthrax toxins. Lastly, our study demonstrates for the first time that anthrax induced neutrophil extracellular trap (NET) formation.
Highlights
Bacillus anthracis is the causative agent of anthrax, and can infect hosts via respiratory, cutaneous, and gastrointestinal routes
Significantly higher levels of the neutrophil chemokine KC were detected in the neutrophil-depleted mice, an effect that may be mediated by a negative feedback loop (Figure 1D)
Previous in vitro studies on the effect of purified anthrax toxins have shown the potential for higher level toxin exposure to inhibit neutrophil chemotaxis, reactive oxygen species (ROS) release, and phagocytosis, suggesting that this strategy might be employed by the pathogen to weaken the immune response (O’brien et al, 1985; Crawford et al, 2006; Szarowicz et al, 2009; Weiner et al, 2014)
Summary
Bacillus anthracis is the causative agent of anthrax, and can infect hosts via respiratory, cutaneous, and gastrointestinal routes. B. anthracis produces a number of virulence factors, the most extensively studied of which is the tripartite anthrax toxin. Anthrax toxin is composed of the receptor binding protective antigen (PA), the metalloprotease lethal factor (LF) and the calmodulin-dependent adenylate cyclase edema factor (EF). The combination of PA and LF generates lethal toxin (LT), which cleaves and inactivates members of the mitogen-activated protein kinase kinase (MEK) family and inflammasome sensor protein NLRP1 in host cells (Duesbery et al, 1998; Levinsohn et al, 2012). PA interacts with EF to create edema toxin (ET), which raises intracellular cAMP levels to promote cation efflux and impair endosomal recycling, leading to edema and disruption of barrier function (Leppla, 1982; Guichard et al, 2010).
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