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 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.  Our evidence indicates that the genetic factor(s) accounting for this early response also plays role in resistance to spore challenge establishing the significance of this phenotype.  We propose to study the early phenotype of advance the understanding of early phathophysiolgical mechanisms and to reveal genetic factors that influence the presentation of LT induced disease well as resistance to spores.  First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., positional cloning and expression QTL analysis).  Second, the pathophysiological mechanism driving the early phenotype will be determined by studies that include intravital microscopy and pharmacological approaches.  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 or spore challenge.