Abstract
Bacillus anthracis infects hosts as a spore, germinates, and disseminates in its vegetative form. Production of anthrax lethal and edema toxins following bacterial outgrowth results in host death. Macrophages of inbred mouse strains are either sensitive or resistant to lethal toxin depending on whether they express the lethal toxin responsive or non-responsive alleles of the inflammasome sensor Nlrp1b (Nlrp1bS/S or Nlrp1bR/R, respectively). In this study, Nlrp1b was shown to affect mouse susceptibility to infection. Inbred and congenic mice harboring macrophage-sensitizing Nlrp1bS/S alleles (which allow activation of caspase-1 and IL-1β release in response to anthrax lethal toxin challenge) effectively controlled bacterial growth and dissemination when compared to mice having Nlrp1bR/R alleles (which cannot activate caspase-1 in response to toxin). Nlrp1bS-mediated resistance to infection was not dependent on the route of infection and was observed when bacteria were introduced by either subcutaneous or intravenous routes. Resistance did not occur through alterations in spore germination, as vegetative bacteria were also killed in Nlrp1bS/S mice. Resistance to infection required the actions of both caspase-1 and IL-1β as Nlrp1bS/S mice deleted of caspase-1 or the IL-1 receptor, or treated with the Il-1 receptor antagonist anakinra, were sensitized to infection. Comparison of circulating neutrophil levels and IL-1β responses in Nlrp1bS/S,Nlrp1bR/ R and IL-1 receptor knockout mice implicated Nlrp1b and IL-1 signaling in control of neutrophil responses to anthrax infection. Neutrophil depletion experiments verified the importance of this cell type in resistance to B. anthracis infection. These data confirm an inverse relationship between murine macrophage sensitivity to lethal toxin and mouse susceptibility to spore infection, and establish roles for Nlrp1bS, caspase-1, and IL-1β in countering anthrax infection.
Highlights
Anthrax disease occurs following germination of Bacillus anthracis spores that enter an animal host through inhalational, oral, or cutaneous routes
An initial survey of subcutaneous infection of 11 inbred mouse strains with the Ames 35 (A35) B. anthracis strain at four doses (16108, 26107, 26106 and 26105 spores/mouse) identified a range of sensitivities to infection (Fig. 1, and data not shown)
We previously used anthrax toxin receptor knockout mice to demonstrate that anthrax toxin is essential for bacterial dissemination in the complement-sufficient C57BL/6 (Nlrp1bR/R) background [13]
Summary
Anthrax disease occurs following germination of Bacillus anthracis spores that enter an animal host through inhalational, oral, or cutaneous routes. Anthrax lethal toxin (LT), responsible for the lethality associated with terminal anthrax disease, is composed of two polypeptides. LF (lethal factor, a protease) is transported into the cytosol by PA (protective antigen, the cell-binding component). LF cleaves members of the mitogen-activated protein kinase kinase family (MEKs) [1,2]. LF’s proteolytic activity is required for its ability to induce vascular collapse in animals and for the rapid lysis of macrophages and dendritic cells from certain inbred rodent strains (for review see [3]). The link between the cleavage of MEKs and LT’s cytotoxic effects in macrophages and animals is currently unknown
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