Novel Therapeutic and Prophylactic Modalities to Protect the United States Armed Forces Against Major Biological Threat Agents

摘要

Secreted virulence factors in addition to lethal toxin (LT) play an important role in anthrax and have previously been identified by us as candidate targets of post-exposure therapies. However the molecular substrates and specific pathogenic mechanisms of these factors remain largely unknown. During the year 2005 the data generated using epithelial cells in culture and mice challenged with B. anthracis spores allow conclude that acceleration of ectodomain shedding by LT other proteolytic proteins and hemolysis represents a new previously unknown feature of anthrax infection. Secreted pathogenic factors of B. anthrax can cause ectodomain shedding likely resulting in protective barriers disruption and tissue penetration by bacilli. In addition proteolysis of the extracellular matrix can play signaling role as a mediator of lethality perturbing different mechanisms of the host defense response including the activation of TLRs. Data on pharmacological inhibition of shedding favor a hypothesis that activities of tested bacterial shedding inducers converge on the stimulation of cytoplasmic tyrosine kinases of the Syk family ultimately leading to activation of cellular sheddase. Both LT and poreforming hemolysin 0 transiently modulate ERK1/2 and p38 MAPK signaling pathways while JNK pathway seems to be irrelevant to accelerate shedding. The concerted acceleration of shedding by several virulence factors could represent a pathogenic mechanism contributing to hemorrhage edema and abdominal cell signaling during anthrax infection.