title: The Trypanosoma cruzi protease cruzain mediates immune evasion.
abstract: Trypanosoma cruzi is the causative agent of Chagas' disease. Novel chemotherapy with the drug K11777 targets the major cysteine protease cruzain and disrupts amastigote intracellular development. Nevertheless, the biological role of the protease in infection and pathogenesis remains unclear as cruzain gene knockout failed due to genetic redundancy. A role for the T. cruzi cysteine protease cruzain in immune evasion was elucidated in a comparative study of parental wild type- and cruzain-deficient parasites. Wild type T. cruzi did not activate host macrophages during early infection (<60 min) and no increase in ∼P iκB was detected. The signaling factor NF-κB P65 colocalized with cruzain on the cell surface of intracellular wild type parasites, and was proteolytically cleaved. No significant IL-12 expression occurred in macrophages infected with wild type T. cruzi and treated with LPS and BFA, confirming impairment of macrophage activation pathways. In contrast, cruzain-deficient parasites induced macrophage activation, detectable iκB phosphorylation, and nuclear NF-κB P65 localization. These parasites were unable to develop intracellularly and survive within macrophages. IL 12 expression levels in macrophages infected with cruzain-deficient T. cruzi were comparable to LPS activated controls. Thus cruzain hinders macrophage activation during the early (<60 min) stages of infection, by interruption of the NF-κB P65 mediated signaling pathway. These early events allow T. cruzi survival and replication, and may lead to the spread of infection in acute Chagas' disease.
authors: Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America.
authors: Patricia S
authors: PS
authors: Doyle
authors: Yuan M
authors: YM
authors: Zhou
authors: Ivy
authors: I
authors: Hsieh
authors: Doron C
authors: DC
authors: Greenbaum
authors: James H
authors: JH
authors: McKerrow
authors: Juan C
authors: JC
authors: Engel
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D057131:Immune Evasion / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines; D015800:Protozoan Proteins / Q000502:physiology*; D014105:Tosyl Compounds; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000235:genetics; D014753:Vinyl Compounds / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010879:Piperazines; D015800:Protozoan Proteins; D014105:Tosyl Compounds; D014753:Vinyl Compounds; D018664:Interleukin-12; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D001119:Arginase