Abstract
Immunosuppression associated with infections of nematode parasites has been documented. Cysteine protease inhibitor (CPI) released by the nematode parasites is identified as one of the major modulators of host immune response. In this report, we demonstrated that the recombinant CPI protein of Ascaris lumbricoides (Al-CPI) strongly inhibited the activities of cathepsin L, C, S, and showed weaker effect to cathepsin B. Crystal structure of Al-CPI was determined to 2.1 Å resolution. Two segments of Al-CPI, loop 1 and loop 2, were proposed as the key structure motifs responsible for Al-CPI binding with proteases and its inhibitory activity. Mutations at loop 1 and loop 2 abrogated the protease inhibition activity to various extents. These results provide the molecular insight into the interaction between the nematode parasite and its host and will facilitate the development of anthelmintic agents or design of anti-autoimmune disease drugs.
Highlights
Nematode parasite infections that are highly prevalent in many parts of the world cause significant health problems [1]
The cDNA library of A. lumbricoides was screened by RT-PCR using the primers for consensus sequences of cystatins reported in other nematode parasites, and a fragment of the Cysteine protease inhibitor (CPI) gene was obtained
We investigated the structural basis of the immunomodulatory function of CPI from A. lumbricoides
Summary
Nematode parasite infections that are highly prevalent in many parts of the world cause significant health problems [1]. Infections of these parasites are often characterized by a chronic and asymptomatic course due to the immunosuppression induced by the parasites in the hosts [2]. The nematode-induced immunosuppression is manifested as protection from autoimmune and allergic diseases [3,4]. The parasitic nematode extracts were proposed as potential therapeutic agents for treatment of autoimmune disorders and allergic diseases [8,9]
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