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Description:
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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 -á 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 . |