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.
Highlights
Trypanosoma cruzi is the parasitic agent of Chagas’ disease that affects approximately 12 million people throughout Latin America (WHO)
Macrophages are the first cells that become infected by T. cruzi and disseminate the infection to other tissues
We report a role for the parasitic protease in immune evasion
Summary
Trypanosoma cruzi is the parasitic agent of Chagas’ disease that affects approximately 12 million people throughout Latin America (WHO). T. cruzi infection is classically transmitted by an insect vector, the reduviid bug [4]. Parasites disseminate from the insect bite site and, in the most common clinical course of Chagas’ disease, infect cardiac myocytes leading to acute myocarditis or chronic infection with relentless cardiac failure. Parasites may be found in many organs, and a highly fatal meningoencephalitis often ensues. These observations led us to hypothesize that T. cruzi successfully evades the host immune response, and may utilize unresponsive macrophages as a means of egress from the insect bite site prior to dissemination to other cell types [5]. While the specific mechanisms of immune evasion by T. cruzi remain largely unknown, several reports have suggested that the major protease of T. cruzi, cruzain, (a.k.a. cruzipain, GP57/51) is a key factor [6,7]
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