Pathophysiological Actions of Anthrax Virulence Determinants

National Institute Of Allergy And Infectious Diseases

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Abstract

LT cleavage and inactivation of the MKK pathways has been reported to act principally on the cardiovascular system, but details of the damage at the cellular and organ levels are not well understood. We have now shown that LT significantly inhibits central metabolism in cardiomyocytes and endothelial cells by downregulating c-Myc expression through the inhibition of the ERK pathway. c-Myc is crucial for regulating metabolic enzymes in glycolysis and the tricarboxylic acid cycle. LT-induced bioenergetic collapse, particularly in cardiomyocytes, impairs the ATP production necessary for cardiac contraction, leading to lethality. Anthrax infections are not easily distinguished from other infections and can progress rapidly. Even if recognized and treated with antibiotics, the toxin proteins may have accumulated to dangerous levels inside cells, where they are inaccessible to many therapeutic agents (e.g, monoclonal antibodies). Disruption of the MKK and c-myc pathways by LT follows from toxin internalization into cells. Therapies for LT-induced damage after host cell internalization of the toxin are lacking. In cells and mice constructed to contain MKK2, MKK3, and MKK6 variants with the LF cleavage sites altered, it was shown that the ERK and p38 pathways remain active and promoted cell and mouse survival after LT challenge. Furthermore, the MEK variant transgenic mice also had increased survival after infection with B. anthracis. Thus, LT-mediated disruption of both ERK and p38 pathway is essential for anthrax pathogenesis. Then, in an unprecedented experiment, we showed that engagement of upstream receptor tyrosine kinases reactivated the LT-disrupted ERK pathway. Administration of a cocktail of the EGF, GM-CSF and FGF2 growth factors significantly increased survival of LT- and B. anthracis-challenged mice. These findings suggest a novel and hopeful strategy for rescuing anthrax infected patients late in the course of disease.