Immunoevasion tactics of Bacillus anthracis

Bacillus anthracis, the etiological agent of anthrax, produces two proteinaceous toxins that contribute to virulence of the bacterium. Lethal toxin (LeTx) is a zinc metalloprotease that cleaves the NH2-terminal region of mitogen-activated kinase kinases. Edema toxin (EdTx) is a bacterial adenylyl cyclase that converts ATP to cAMP. These toxins have been shown to have immunosuppressive properties that allow B. anthracis to evade host immune cells. To further elucidate that mechanism of immune evasion, we tested the hypothesis that B. anthracis toxins inhibit the innate and adaptive immune responses of the host by disrupting the activation of p38 in macrophages and T lymphocytes.; Genechip and real-time reverse transcriptase-polymerase chain reaction analysis identified Regulator of G-protein signaling 16 (rgs16), the product of which attenuates the activation of the mitogen-activated kinase, p38, as being induced during the intoxication process of macrophages treated with LeTx. However, the gene was not induced in primary peritoneal macrophages suggesting the induction of rgs16 was a phenomenon limited to the transformed cell line.; EdTx inhibited lipopolysaccharide and peptidylglycan induced production of TNF-alpha and IL-12 in vitro. The toxin also obliterated the phagocytic activity of RAW 264.7 cells. Analysis of the phosphorylation status of p38 suggested that, EdTx, like LeTx, inhibited the activation of this signaling molecule in macrophages.; To determine the effects of the anthrax toxins on the adaptive immune response, T lymphocytes were exposed to LeTx or EdTx in vitro or in vivo. Both toxins inhibited the activation of CD4 + T cells when present at the time of activation. Injection of sublethal doses of either LeTx or EdTx into mice directly inhibited the subsequent activation of T lymphocytes isolated from toxin-injected mice after 24 h. The phosphorylation of p38 was suppressed in LeTx-treated mice but not in EdTx-treated mice, suggesting that EdTx-mediated suppression of T cell activation was independent of p38 inhibition.; The research presented in this report illustrates the inhibitory effects of LeTx and EdTx on macrophages and T lymphocytes, providing valuable insight into the immunoevasion tactics of B. anthracis.