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 (Nlrp1b(S/S) or Nlrp1b(R/R), respectively). In this study, Nlrp1b was shown to affect mouse susceptibility to
infection. Inbred and congenic mice harboring macrophage-sensitizing Nlrp1b(S/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 Nlrp1b(R/R) alleles (which cannot activate
caspase-1 in response to toxin). Nlrp1b(S)-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 Nlrp1b(S/S) mice. Resistance to
infection required the actions of both caspase-1 and IL-1β as Nlrp1b(S/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 Nlrp1b(S/S),Nlrp1b(R/) (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 Nlrp1b(S), caspase-1, and IL-1β in countering
anthrax infection.