Debridement increases survival in a mouse model of subcutaneous anthrax.

Anthrax is caused by infection with Bacillus anthracis, a spore-forming gram-positive bacterium. A major virulence factor for B. anthracis is an immunomodulatory tripartite exotoxin that has been reported to alter immune cell chemotaxis and activation. It has been proposed that B. anthracis infections initiate through entry of spores into the regional draining lymph nodes where they germinate, grow, and disseminate systemically via the efferent lymphatics. If this model holds true, it would be predicted that surgical removal of infected tissues, debridement, would have little effect on the systemic dissemination of bacteria. This model was tested through the development of a mouse debridement model. It was found that removal of the site of subcutaneous infection in the ear increased the likelihood of survival and reduced the quantity of spores in the draining cervical lymph nodes (cLN). At the time of debridement 12 hours post-injection measurable levels of exotoxins were present in the ear, cLN, and serum, yet leukocytes within the cLN were activated; countering the concept that exotoxins inhibit the early inflammatory response to promote bacterial growth. We conclude that the initial entry of spores into the draining lymph node of cutaneous infections alone is not sufficient to cause systemic disease and that debridement should be considered as an adjunct to antibiotic therapy.

Regulation of learning and memory by meningeal immunity: a key role for IL-4.

Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell-based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4-producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell-derived IL-4 was critical, as IL-4(-/-) mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4(-/-) bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4(-/-) mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell-derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline.