New insights into the pathogenesis and treatment of anthrax toxin-induced shock.
Inhalational Bacillus anthracis infection is a leading bioterrorist health threat in the US today. Lethal (LeTx) and edema toxin production are key to the virulent effects of this lethal bacteria. Recent insights into the structure and function of these toxins have increased the understanding of both the pathogenesis and treatment of anthrax. These are binary type toxins comprised of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. Primary cellular receptors for protective antigen have been identified and the processing of the completed toxins clarified. Consistent with the ability of lethal factor to cleave mitogen activated protein kinase kinases, the evidence indicates that an excessive inflammatory response does not contribute to shock with LeTx. Rather, the immunosuppressive effects of LeTx could promote infection; however, direct endothelial dysfunction may have an important role in shock due to LeTx. Recent studies show that edema factor, a potent adenyl cyclase, may have a major role in shock during anthrax and that it may also be immunosuppresive. Therapies under development which target several steps in the cellular uptake and function of these two toxins have been effective in both in vitro and in vivo systems. Understanding how best to apply these agents in combination with conventional treatments should be a goal of future research.
Li
Yan
Y
National Institutes of Health, Critical Care Medicine Department, Clinical Center, Bethesda, MD 20892, USA.
Sherer
Kevin
K
Cui
Xizhong
X
Eichacker
Peter Q
PQ
D000262:Adenylyl Cyclases / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000881:Anthrax / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D022122:Anthrax Vaccines / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D001408:Bacillus anthracis / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000382:microbiology / Q000503:physiopathology; D006801:Humans; D018000:Receptors, Peptide / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D014774:Virulence
D022122:Anthrax Vaccines; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors; D000262:Adenylyl Cyclases