Death from systemic anthrax in humans results from massive inflammation, multi-organ failure and shock caused by harmful levels of Bacillus anthracis exotoxins. Early antibiotic treatment can improve survival by eliminating infectious organisms, however, most victims succumb because antibiotics are administered too late in the course of anthrax infection when toxins have already reached critically high levels. It is our hypothesis that, in addition to the direct effects of the anthrax toxins, specific proinflammatory cytokines produced in response to infection with B. anthracis contribute significantly to the pathogenesis of systemic disease. In our proposed study, we will define the proinflammatory cytokine cascade in B. anthracis-infected monocytes in vitro, in mice infected by inhalation of B. anthracis and in rabbits with anthrax meningitis. We will investigate whether inhibition of the production of specific proinflammatory cytokines improves outcome in these animal models of B. anthracis infection and treatment. In particular, we will study the effects of antibiotics combined with immunomodulatory drugs (thalidomide analogues) on the pathogenesis of anthrax meningitis, reported in 50% of human cases of systemic anthrax and associated with long term CNS damage and impaired cognitive functions in survivors of this condition. We have access to suitable BL3 facilities, experience in working with virulent clinical isolates of Mycobacterium tuberculosis both in vitro (in cultured fresh human monocytes) and in vivo (in mouse and rabbit models of infection), and access to novel immunomodulatory drugs (thalidomide analogues). Thus we are in a unique position to conduct the proposed studies. We believe that an improved understanding of the cytokine cascade which may be exacerbated by products released from bacilli killed by antibiotic treatment, and better insight into the contribution of cytokines to the pathology of anthrax will enable the design of superior treatment regimens as clinical countermeasures using antibiotics supplemented by selected immunomodulatory drugs.