Role ofBacillus anthracis Spore Structures in Macrophage Cytokine Responses

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Abstract
The innate immune response of macrophages (Mφ) to spores, the environmentally acquired form ofBacillus anthracis, is poorly characterized. We therefore examined the early Mφ cytokine response toB. anthracisspores, before germination. Mφ were exposed to bacilli and spores of Sterne strain 34F2 and its congenic nongerminating mutant (ΔgerH), and cytokine expression was measured by real-time PCR and an enzyme-linked immunosorbent assay. The exosporium spore layer was retained (exo+) or removed by sonication (exo−). Spores consistently induced a strong cytokine response, with the exo−spores eliciting a two- to threefold-higher response than exo+spores. The threshold for interleukin-1β (IL-1β) production by wild-type Mφ was significantly lower than that required for tumor necrosis factor alpha expression. Cytokine production was largely dependent on MyD88, suggesting Toll-like receptor involvement; however, the expression of beta interferon in MyD88−/−Mφ suggests involvement of a MyD88-independent pathway. We conclude that (i) theB. anthracisspore is not immunologically inert, (ii) the exosporium masks epitopes recognized by the Mφ, (iii) the Mφ cytokine response toB. anthracisinvolves multiple pattern recognition receptors and signaling pathways, and (iv) compared to other cytokines, IL-1β is expressed at a lower spore concentration.