The recent deliberate dissemination of anthrax spores has revealed significant gaps in our knowledge of anthrax pathogenesis. In anthrax infection, as in other inflammatory diseases, the macrophage can play opposing roles. Macrophages serve to limit the infection by ingesting and eliminating the spores and vegetative bacilli, but they can also be a reservoir for replication and dissemination of the bacteria. In this grant we will use recently developed murine genetic models to clarify the role of the macrophage in anthrax pathogenesis. We will establish the time course of leukocyte migration to the lungs and draining mediastinal lymph nodes of mice infected with pulmonary anthrax, and we will identify the signals responsible for this recruitment. Previous work from our group has established that the monocyte chemoattractant protein (MCP) family of chemokines and their receptor, chemokine receptor 2 (CCR2), play pivotal roles in the migration of macrophages and dendritic cells to sites of inflammation, and that they are essential for host survival after infection with Mycobacterium tuberculosis. Unlike M. tuberculosis, a prominent feature of infection with Bacillus anthracis is the systemic effects produced by anthrax toxin (ATX) acting on the macrophages. Thus in the case of anthrax, it is unclear if impaired macrophage trafficking would be detrimental, or perhaps even beneficial to the host. We will take advantage of our CCR2-/- mice to directly address these possibilities in a model of pulmonary anthrax. These experiments will reveal whether paradigms established for the pathogenesis of M. tuberculosis apply to B. anthracis. We will also compare the responses of CCR2-/- and CCR2+/+ mice to lethal toxin a component of ATX. Finally, we will attempt to produce a mouse model of cutaneous anthrax infection. Completion of the specific aims of this pilot grant will establish the kinetics of leukocyte trafficking in pulmonary anthrax, will determine if chemokines such as MCP-1 play an important role in macrophage trafficking and host survival in pulmonary anthrax, and may provide a rationale for the use of chemokine/chemokine receptor antagonists in the treatment of anthrax. ? ?
