Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

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ABSTRACT Virulence of Bacillus anthracis is associated with the secretion of three plasmid-encoded toxin proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). LF and EF are catalytic moieties that share the receptor-binding subunit, PA. As a result, two binary toxins are formed: lethal toxin (LT) consisting of PA and LF, and edema toxin (ET) consisting of PA and EF. Injection of purified LT into animals induces many of the pathologies associated with fulminate anthrax infection indicating that this toxin plays a significant role in disease. However, there is a lack of consensus about how LT causes these pathologies. In response to LT injection, a rapidly induced phenotype was identified in a congenic strain of mice that has a chromosomal segment of the CAST/EiJ strain on an otherwise C57BL/6J background. Study of this strain will advance the understanding of the mechanism(s) underlying early pathophysiological changes and reveal genetic factors that influence LT induced disease. In addition, this strain recovers from their precipitous decline only to subsequently succumb to LT. The dramatic recovery provides a unique window to investigate host responses that suppress or counter LT induced disease. We propose to study the early LT-response phenotype in these animals. First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., candidate gene, positional cloning, and expression QTL analysis) with the eventual Objective being the identification of the gene(s) responsible for the early phenotype. Second, the pathophysiological mechanism driving the early phenotype, and recovery from it, will be determined by studies that include intravital microscopy, bone marrow transplantation, pathological and clinical chemistry profiles, and gene chip arrays that are focused on recovery phase, stress response pathways. In summary, the early responding congenic strain will be a powerful tool for: 1) identifying genetic factors that regulate sensitivity to LT, 2) elucidating the pathophysiological mechanisms associated with early LT-induced events, and 3) revealing defense mechanisms that are employed by the host in response to LT.