Chitinase Dependent Control of Protozoan Cyst Burden in the Brain

Abstract

Chronic infections represent a continuous battle between the host's immune system and pathogen replication. Many protozoan parasites have evolved a cyst lifecycle stage that provides it with increased protection from environmental degradation as well as endogenous host mechanisms of attack. In the case of Toxoplasma gondii, these cysts are predominantly found in the immune protected brain making clearance of the parasite more difficult and resulting in a lifelong infection. Currently, little is known about the nature of the immune response stimulated by the presence of these cysts or how they are able to propagate. Here we establish a novel chitinase-dependent mechanism of cyst control in the infected brain. Despite a dominant Th1 immune response during Toxoplasma infection there exists a population of alternatively activated macrophages (AAMØ) in the infected CNS. These cells are capable of cyst lysis via the production of AMCase as revealed by live imaging, and this chitinase is necessary for protective immunity within the CNS. These data demonstrate chitinase activity in the brain in response to a protozoan pathogen and provide a novel mechanism to facilitate cyst clearance during chronic infections.

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

“…Further, it was previously demonstrated that M2 have anti-cyst activity (40). We assessed whether a shift in proportions to favor M2 improved regeneration in part through decreasing parasite burden.…”

“…While the depletion of Tregs may affect total parasitic activity, we do not observe significant overall alterations in the parasite burden following depletion as measured by the B1 gene. Previous studies have shown that M2 have anti-cyst properties during T. gondii infection in the brain (40). Interestingly, we show that following Treg depletion, increases in M2 proportions are associated with decreased expression of the bradyzoite gene bag1 .…”

Cerebral complement C1q activation in chronic Toxoplasma infection

“…When infection enters a chronic phase, tissue cysts are formed and predominantly located in the CNS for the lifetime of the host. Such persistence of tissue cysts requires a continuous immune response provided by resident CNS and/or infiltrating peripheral immune cells to prevent cyst reactivation and toxoplasmic encephalitis (Nance et al, 2012). It is possible that C1q is one such factor involved in this long-term, anti-parasite immune response.…”

Co-existence of classical and alternative activation programs in macrophages responding to Toxoplasma gondii

“…Recently, macrophages expressing an alternatively activated phenotype have been discovered to reside in the brain of T. gondii -infected mice. These cells mediate parasite cyst lysis via their production of chitinase (Nance et al, 2012). Our analysis of the phenotype of macrophages activated by T. gondii in the peritoneal cavity suggest that, instead of distinct M1 and M2 subpopulations, the chitinase-expressing macrophages could themselves be expressing the classical activated program activated by IFN-γ.…”