Pathogenesis and host resistance in anthrax

Lethal toxin (LF + PA) and edema toxin (EF + PA) are now regarded as being responsible for the characteristic symptoms and course of anthrax. LF + PA is cytolytic for mouse peritoneal macrophages and kills certain mouse macrophage cell lines; EF + PA impairs the phagocytic function of neutrophils but EF + PA, LF + PA, or EF + LF + PA stimulate neutrophil chemotaxis.

There has long been fascination over the seemingly inverse relationship between susceptibility to toxin and susceptibility to infection. Rats, for example, are highly susceptible to the toxin (LDi0 (median lethal dose) of Fischer 344 rat = 0.5 (jug LF + -2.5 |xg PA) but highly resistant to the infection (intramuscular LD,0 ~ 106 spores), while guinea pigs are relatively resistant to the toxin (LD„, = 50 LF + ~ 250 |xg PA) but highly susceptible to infection (intramuscular LD,0 <10 spores). The underlying host defense mechanisms responsible for this paradox have not been elucidated but it indicates that resistance to infection may involve a separate mechanism than that required for resistance to lethal toxicity. If resistance to infection is due to the number and availability of macrophages then this protective mechanism would also provide a larger target population of macrophages for the effect of LF toxin.

The in vivo depletion of mouse macrophages by the use of repeated injections of silica has elucidated the key role macrophages play in the disease process. BALB/c mice depleted of macrophages are resistant to lethal toxin (LT) but can be made sensitive to it by adoptive transfer of 108 RAW264.7 cells (a toxin-sensitive monocyte/macrophage cell line). The in vivo transfer of the same number of the LT-resistant mouse macrophage line IC-21 cells does not restore sensitivity. Resistant cells have been shown to possess normal numbers of receptors for PA and are able to activate PA and bind and internalize LF and EF. In addition, introduction of LF into the cytosol of resistant cells does not result in cell death, indicating that these cells may lack the cytosolic target of LF. Genetic studies involving resistance to nonencapsu-lated bacilli indicate that resistance may be controlled by a single dominant locus or gene complex.

Analysis of cytokine levels produced by RAW264.7 cells in vitro has revealed that levels of LT as low as 10"9 pg mL1 LF with 0.1 |xg ml"' PA induce synthesis of high levels of tumour necrosis factor (TNF) and interleukin-1. Neutralizing antisera to each of these cytokines injected into mice 24 hours before challenge with LT provides partial protection, while complete protection is achieved when the anti-sera are combined. These results strongly implicate the release of these factors in the cause of death of toxin-treated animals by a septic shock-type mechanism. Whether this and differences in susceptibilities of macrophages to LF + PA/EF + PA are related beyond mouse models to inter- and intraspec-ies differences in susceptibility to B. anthracis or its toxin remains to be determined.

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