Described here is a novel mechanism of protozoan cyst clearance in the CNS during chronic infection. These data show the presence of a population of alternatively activated macrophages in the brain that secrete the active chitinase, AMCase, in response to chitin in the cyst wall. Using both chemical and genetic inhibition in vitro, it is revealed that this enzyme is required for efficient degradation and destruction of the cyst. The necessity for AMCase is demonstrated in vivo, as the absence of the enzyme resulted in a significant increase in cyst burden and decrease in survival during chronic infection. Together, these data identify an important mechanism of parasite control and cyst clearance in the CNS. Currently, no therapies exist that lead to the total clearance of this parasite from the brain. Therefore, developing an understanding of the natural mechanisms of cyst clearance has the potential to lead to new and effective therapies for this and other chronic infections. alternative activation of macrophages in the CNS. Since latent cysts are the most prevalent form of infection in the brain, an attractive candidate for the source of this stimulus is the presence of chitin in the cyst wall [49, 50] as it has been shown that the presence of chitin induces the recruitment of macrophages that have an alternatively activated phenotype [51, 52] . To determine if sources of T. gondii can induce alternative activation, tachyzoites, bradyzoites, and cysts were added to bone marrow derived macrophage (BMDM) cultures and the production of urea, a downstream product of arginase activity, was measured [53] . In addition, soluble antigen derived from freeze-thawed tachyzoites (sTAg) and whole cysts (cystAg) was assessed for their ability to induce urea (Figure 2A) . Our results show a baseline production of urea in unstimulated (media) macrophage cultures, possibly due to the presence of M-CSF [54] . This significantly increased (p,0.001) during AAMØ polarization with IL-4. Despite the known ability of tachyzoites to induce arginase production [46] , tachyzoite infection of macrophages did not lead to significant production of urea ( Figure 2A ). This can be attributed to the use of a type II strain which is a weak inducer of arginase-1 [47, 48] . Importantly, addition of cysts or cyst antigen but not ''naked'' bradyzoites, did lead to a significant increase in urea production although not as great as induction of alternative activation by IL-4 [38, 55] . This points to components of the cyst wall as the stimulus for AAMØ. Taken together, these data demonstrate that macrophages can be alternatively activated by the presence of T. gondii cysts, but not free replicating parasites.