This project focuses on identifying the factors that determine human susceptibility to bioweaponsagents. This is an imPortant goal, as we need to be able to identify high-risk groups in order to targeteffective preventive measures. Evidence from human and animal studies supports the concept that hostfactors, some of which are genetically determined, are important modifiers of susceptibility to diseasessuch as malaria and meningococcal infection. There is considerable evidence demonstrating person toperson variability in innate immune inflammatory responses to bacterial products. This variability islikely to extend to innate immune inflammatory responses to products of bacteria that may be used asbioweapons agents and could influence outcomes after exposure to such agents. An understanding ofthe molecular mechanisms underlying human variability in innate immune inflammatory responses tothese agents may help to prospectively identify populations at high-risk for poor outcomes after abioweapons attack. This would aid in the optimal allocation of resources and may identify newtherapeutic targets. We propose to measure the variability in innate immune responses to Y. pestis andother potential bioweapons agents using an in vitro model of whole blood responses to bacterialproducts. We will investigate the magnitude of the genetic component of this variability through aclassical twins study. We will determine the extent to which specific allelic haplotypes contribute tothis variability. Finally, we will identify innate immune response profiles in patients with chronicrespiratory diseases, a population that is likely to be at high-risk for poor outcomes in the event ofexposure to aerosolized Y. pestis and other bioweapons agents. Our initial emphasis will be on Y.pestis, but the approaches developed in these studies will be adapted to subsequent studies of otherpotential bioweapons agents.
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