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Infection and Immunity, March 2003, p. 1274-1280, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1274-1280.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Surface Amebic Cysteine Proteinase Inactivates Interleukin-18

Xuchu Que,1 Soo-Hyun Kim,2 Mohammed Sajid,3 Lars Eckmann,4 Charles A. Dinarello,2 James H. McKerrow,3 and Sharon L. Reed1,4*

Departments of Pathology,1 Medicine, University of California, San Diego, California 92103,4 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262,2 Department of Pathology, University of California, San Francisco, California 941423

Received 13 September 2002/ Returned for modification 5 October 2002/ Accepted 25 November 2002

Amebiasis is a major cause of morbidity and mortality worldwide. Invasion by Entamoeba histolytica trophozoites causes secretion of proinflammatory cytokines from host epithelial cells, leading to a local acute inflammatory response, followed by lysis of colonic cells. Extracellular cysteine proteinases from amebic trophozoites are key virulence factors and have a number of important interactions with host defenses, including cleavage of immunoglobulin G (IgG), IgA, and complement components C3 and C5. Amebic lysates have also been shown to activate the precursor to interleukin 1-beta (proIL-1ß), mimicking the action of caspase-1. IL-18 is also a central cytokine, which induces gamma interferon (IFN-{gamma}) and activates macrophages, one of the main host defenses against invading trophozoites. Because proIL-18 is also activated by caspase-1, we evaluated whether amebic proteinases had a similar effect. Instead, we found that recombinant proIL-18 was cleaved into smaller fragments by the complex of surface-associated and released amebic proteinases. To evaluate the function of an individual proteinase from the complex pool, we expressed an active surface proteinase, EhCP5, which is functional only in E. histolytica. Recombinant EhCP5 expressed in Pichia pastoris had kinetic properties similar to those of the native enzyme with respect to substrate specificity and sensitivity to proteinase inhibitors. In contrast to the activation of proIL-1ß by amebic lysates, the purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive fragments. These studies suggest that the acute host response and amebic invasion result from a complex interplay of parasite virulence factors and host defenses. E. histolytica may block the host inflammatory response by a novel mechanism, inactivation of IL-18.

* Corresponding author. Mailing address: Division of Infectious Diseases, UCSD Medical Center, 200 W. Arbor Drive, San Diego, CA 92103-8416. Phone: (619) 543-6146. Fax: (619) 543-6614. E-mail: slreed{at}ucsd.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, March 2003, p. 1274-1280, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1274-1280.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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