Genetic Determinants of Host Susceptibility to Pulmonary Anthrax

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DESCRIPTION (provided by applicant): Due to the existing biothreat of B. anthracis, and its potential to cause high mortality when weaponized for inhalation exposure, there is an increasing interest in understanding the pathogenesis and treatment of pulmonary anthrax. Pulmonary anthrax is usually biphasic in nature, with an insidious onset of flu-like symptoms, followed by rapid deterioration characterized by the development of acute lung injury, often leading to a fatal outcome. There is a critical need to better comprehend the host mechanisms involved in B. anthracis infection of the lung and the pathogenesis of pulmonary anthrax caused by inhalation of anthrax spores. In addition to the known host macrophage sensitivity to anthrax lethal toxin, unknown host factors influence B. anthracis infection and virulence. Our long-term goal is to understand the genetic factors of host susceptibility to B. anthracis spore-induced pulmonary anthrax. Our hypothesis is that inter-individual variability in the development of pulmonary anthrax from exposure to B. anthracis is controlled by host genetic factors that influence the survival time during the infection process. We propose to use multiple inbred mouse strains to investigate this hypothesis. The Specific Aims are: 1) to determine inter-strain differences between inbred mice for survival time during the development of B. anthracis spore-induced pulmonary anthrax, and 2) to identify quantitative trait loci (QTLs) with linkage to survival time of mice developing B. anthracis spore-induced pulmonary anthrax and in silico analysis of the QTLs for initial assessment of the candidate genes. This R21 effort will constitute an initial progress toward a full future effort to thoroughly characterize novel host genetic determinants, and assess functional significance of specific candidate genes to understand host-mediated mechanisms and develop new therapeutics for the treatment of pulmonary anthrax. The proposed research will help understand the genetic basis of inter-individual susceptibility to pulmonary anthrax. The scientific developments could redirect or strengthen first-response and continuing clinical approaches to a pulmonary anthrax biothreat situation, as well as the improvement of risk assessment through the identification of "at risk" populations.