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      Chitinase Dependent Control of Protozoan Cyst Burden in the Brain


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          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.

          Author Summary

          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.

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          Most cited references76

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          Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences.

          Recent studies have described the development of distinct functional subsets of macrophages in association with cancer, autoimmune disease, and chronic infections. Based on the ability of Th1 vs Th2 cytokines to promote opposing activities in macrophages, it has been proposed that macrophages develop into either type 1 inflammatory or type 2 anti-inflammatory subsets. As an alternative to the concept of subset development, we propose that macrophages, in response to changes in their tissue environment, can reversibly and progressively change the pattern of functions that they express. As demonstrated herein, macrophages can reversibly shift their functional phenotype through a multitude of patterns in response to changes in cytokine environment. Macrophages display distinct functional patterns after treatment with IFN-gamma, IL-12, IL-4, or IL-10 and additional functional patterns are displayed depending on whether the cytokine is present alone or with other cytokines and whether the cytokines are added before or concomitantly with the activating stimulus (LPS). Sequential treatment of macrophages with multiple cytokines results in a progression through multiple functional phenotypes. This ability to adapt to changing cytokine environments has significant in vivo relevance, as evidenced by the demonstration that macrophage functional phenotypes established in vivo in aged or tumor-bearing mice can be altered by changing their microenvironment. A concept of functional adaptivity is proposed that has important implications for therapeutic targeting of macrophages in chronic diseases that result in the dominance of particular functional phenotypes of macrophages that play a significant role in disease pathology.
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            Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.

            Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
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              Toxoplasmic encephalitis in AIDS.

              Involvement of the central nervous system (CNS) is common in patients with advanced disease due to human immunodeficiency virus (HIV). Symptoms range from lethargy and apathy to coma, incoordination and ataxia to hemiparesis, loss of memory to severe dementia, and focal to major motor seizures. Involvement may be closely associated with HIV infection per se, as in the AIDS dementia complex, but is frequently caused by opportunistic pathogens such as Toxoplasma gondii and Cryptococcus neoformans or malignancies such as primary lymphoma of the CNS. The clinical presentations of attendant and direct CNS involvement are remarkably non-specific and overlapping, yet a correct diagnosis is critical to successful intervention. Toxoplasmic encephalitis is one of the most common and most treatable causes of AIDS-associated pathology of the CNS. A great deal has been learned in the last 10 years about its unique presentation in the HIV-infected patient with advanced disease. Drs. Benjamin J. Luft of the State University of New York at Stony Brook and Jack S. Remington of the Stanford University School of Medicine and Palo Alto Medical Foundation's Research Institute have studied T. gondii for many years and are two of the leading experts in the field. This commentary comprises an update of their initial review (J Infect Dis 1988;157:1-6) and a presentation of the current approaches to diagnosing and managing toxoplasmic encephalitis in HIV-infected patients.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                November 2012
                November 2012
                29 November 2012
                : 8
                : 11
                : e1002990
                [1 ]Division of Biomedical Sciences, University of California, Riverside, California, United States of America
                [2 ]National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [3 ]Institute for Integrative Genome Biology, University of California, Riverside, California, United States of America
                [4 ]Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts, United States of America
                [5 ]Department of Molecular Biology and Biochemistry, Institute for Immunology, University of California, Irvine, Irvine, California, United States of America
                Cornell University, United States of America
                Author notes

                LF and CH are employed by Pfizer. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. All other authors have declared that no competing interests exist.

                Conceived and designed the experiments: JPN KMV TAW EHW. Performed the experiments: JPN DW CD KMV SN. Analyzed the data: JPN DW CD KMV DC SN CH LF TEL TAW EHW. Contributed reagents/materials/analysis tools: KMV DC CH LF TEL TAW. Wrote the paper: JPN KMV EHW. Provided the AMCase null mice: CH LF.


                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                : 8 May 2012
                : 10 September 2012
                Page count
                Pages: 16
                These studies were supported in part by grants to EHW from CRCC, the UCR Division of Biomedical Sciences, the UCR academic senate and NIH RNS071160A and RNS072298A and to TEL by NIH R01NS041249. TAW is supported by the intramural research program of the National Institute of Allergy and Infectious Diseases/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Immune Defense
                Immunity to Infections
                Innate Immunity
                Immune Response
                Infectious Diseases
                Parasitic Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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