The Trypanosoma cruzi Protease Cruzain Mediates Immune Evasion

PLoS Pathogens

Doron C. Greenbaum¹  James H. McKerrow¹  Juan C. Engel¹  Patricia S. Doyle¹  Yuan M. Zhou¹  Ivy Hsieh¹ 

[1] Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America

关键词: Trypanosoma cruzi;    Parasitic diseases;    Macrophages;    Transcription factors;    Proteases;    Amastigotes;    Epimastigotes;    Chagas disease;   

DOI  :  10.1371/journal.ppat.1002139

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY