Cysteine Proteinases and the Pathogenesis of Amebiasis

Que, Xuchu; Reed, Sharon L.

doi:10.1128/cmr.13.2.196-206.2000

Cited by 206 publications

(110 citation statements)

References 121 publications

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“…Several pathogenic protozoan parasites, including Entamoeba histolytica (5), Leishmania (6 -8), Trypanosoma cruzi (9,10), Trypanosoma congolense (11), and Trypanosoma brucei (12), express multiple CP enzymes (reviewed in Ref. 13).…”

Section: Eishmania Mexicana Like Other New World Leishmaniamentioning

confidence: 99%

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Buxbaum

Denise

Coombs

et al. 2003

The Journal of Immunology

107

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C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Δcpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Δcpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Δcpb-infected IL-12p40−/− and STAT4−/− mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-γ response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.

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Section: Eishmania Mexicana Like Other New World Leishmaniamentioning

confidence: 99%

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Buxbaum

Denise

Coombs

et al. 2003

The Journal of Immunology

107

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“…Despite being unicellular throughout its life cycle, this protist shows remarkable complexity of Rab proteins; it possesses more than 90 Rab genes in the genome, highlighting E. histolytica as an organism with extremely diverse and complex Rab functions Saito-Nakano et al, 2005). Vesicular trafficking plays an This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-04 -0283) on August 24, 2005. indispensable role for this organisms in nutrient uptake by ingestion and degradation of microorganisms in the large intestine, and also in secretion of cyto-and histolytic degradative proteins including cysteine proteases (CP; Que and Reed, 2000) and pore forming peptides (amoebapore: AP; Zhang et al, 2004), both of which have been implicated for colonization in mammalian tissues and evasion from host immune system. CP, consisting of Ͼ30 members of the gene family (Bruchhaus et al, 2003;Tannich, personal communication), is currently considered to be primarily responsible for the pathogenesis of E. histolytica as genes encoding certain isotypes, i.e., CP1 and CP5, are either absent or degenerated in a closely-related but nonpathogenic E. dispar species (Bruchhaus et al, 1996;Willhoeft et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

A Retromerlike Complex Is a Novel Rab7 Effector That Is Involved in the Transport of the Virulence Factor Cysteine Protease in the Enteric Protozoan ParasiteEntamoeba histolytica

Nakada‐Tsukui

Saito‐Nakano

Ali

et al. 2005

MBoC

137

173

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Vesicular trafficking plays an important role in a virulence mechanism of the enteric protozoan parasite Entamoeba histolytica as secreted and lysosomal cysteine protease (CP) contributes to both cytolysis of tissues and degradation of internalized host cells. Despite the primary importance of intracellular sorting in pathogenesis, the molecular mechanism of CP trafficking remains largely unknown. In this report we demonstrate that transport of CP is regulated through a specific interaction of Rab7A small GTPase (EhRab7A) with the retromerlike complex. The amoebic retromerlike complex composed of Vps26, Vps29, and Vps35 was identified as EhRab7A-binding proteins. The amoebic retromerlike complex specifically bound to GTP-EhRab7A, but not GDP-EhRab7A through the direct binding via the carboxy terminus of EhVps26. In erythrophagocytosis the retromerlike complex was recruited to prephagosomal vacuoles, the unique preparatory vacuole of digestive enzymes, and later to phagosomes. This dynamism was indistinguishable from that of EhRab7A, and consistent with the premise that the retromerlike complex is involved in the retrograde transport of putative hydrolase receptor(s) from preparatory vacuoles and phagosomes to the Golgi apparatus. EhRab7A overexpression caused enlargement of lysosomes and decrease of the cellular CP activity. The reduced CP activity was restored by the coexpression of EhVps26, implying that the EhRab7A-mediated transport of CP to phagosomes is regulated by the retromerlike complex. INTRODUCTIONRab GTPases play an essential role to regulate intracellular membrane trafficking. The compartmentalization and functions of Rab proteins are modulated at multiple layers of mechanisms including isoprenylation of the carboxy terminus, nucleotide exchange, and binding of specific effector molecules (Stenmark and Olkkonen, 2001;Takai et al., 2001;Tuvim et al., 2001). Among these modulators, effectors play key roles in the control of 7-90 Rab proteins depending on organisms from fission yeast and amoeba to mammals and plants. A variety of effectors have been identified and shown to interact with specific Rab protein. For instance, regulatory secretions of neurotransmitters from neurons or insulin from pancreatic ␤-cells are regulated by the specific interaction of Rab3 with its effectors (Jahn and Sudhof, 1999). At least four proteins, Rabphilin3, Rim1, Rim2, and Noc2, are known to bind Rab3 and recruit cAMP-GEFII, 14 -3-3, and zyxin, respectively, to regulate cAMP responsiveness, phosphoserine-dependent signaling, and the interaction with cytoskeleton (Kotake et al., 1997;Ozaki et al., 2000;Sun et al., 2003). The specificity of the Rab-effector interaction is attributable to primary sequence motifs in only a few cases including exophilins or Slip/Slac2, Rab3, and Rab27 effectors (Izumi et al., 2003). However, the majority of Rab effectors lack recognizable conserved binding motifs. For instance, Rab5 effectors, rabaptin-5, Rabex-5, EEA1, Rabenosyn-5, hVps34/p150, p110␤/p35␣, rabip4Ј, and rabankyrin-5, which a...

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“…Host-cell apoptosis is detected in amoebic liver-abscess and intestinal disease in mice, suggesting that human intestinal epithelial or liver cells might undergo the same fate (Seydel & Stanley, 1998;Ragland et al, 1994;Huston et al, 2000;Boettner & Petri, 2005). Other factors that also play an important role in pathogenesis are the parasite secreted cysteine proteases (Que & Reed, 2000;Helberg, et al, 2001). E. histolytica cysteine proteinases digest extracellular matrix proteins which facilitate trophozoite invasion into the submucosal tissues and enable their lateral spread (Tavares et al, 2005).…”

Section: E Histolytica Invades Tissue and Causes Clinicalmentioning

confidence: 99%

“…These mediators have several effects including attraction of neutrophils and macrophages to the site of amoebic invasion (Seydel et al, 1997;Stenson et al, 2001). As E. histolytica trophozoites enter into the bloodstream, the trophozoites interact with the complement system; a number of parasite surface molecules such as the complex lipophosphopeptidoglycans (Moody-Haupt et al, 2000) and peroxiredoxin (Choi et al, 2005), as well as proteases (Que & Reed, 2000;Hirata et al, 2007) and the Gal/GalNAcspecific lectin (Braga et al, 1992), are implicated in resisting this attack. Trophozoites reaching the liver create unique abscesses, and the lysis of neutrophils by E. histolytica trophozoites release mediators that lead to hepatocyte death (Burchard et al, 1993).…”

Section: E Histolytica Invades Tissue and Causes Clinicalmentioning

confidence: 99%

“…Compelling evidence is now available which clearly shows that CPs are one of the main culprits for the pathology caused by the pathogen. Some of the CPs have been shown to be involved in pathogenicity such as destruction of host tissue or triggering an inflammatory response in the infected individual (Que & Reed, 2000;Stanley, 2003). Other CPs were shown to be essential for intracellular protein turnover and degradation as well as for life cycle processes such as encystation and excystation (Makioka et al, 2005).…”

Section: Cysteine Proteinases (Cps)mentioning

confidence: 99%

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Trophozoites ofEntamoeba histolyticaepigenetically silenced in several genes are virulence-attenuated

2008

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Summary :The human intestinal parasite Entamoeba histolytica causes amoebic colitis and amoebic liver abscesses. Three classes of amoebic molecules have been identified as the major virulence factors, the Gal/GalNAc inhibitable lectin that mediates adherence to mammalian cells, the amoebapores which cause the formation of membrane ion channels in the target cells and the cysteine proteinases which degrade the matrix proteins, the intestinal mucus and secretory IgA. Transcriptional silencing of the amoebapore (Ehap-a) gene occurred after transfection of trophozoites with a plasmid containing a segment of the 5' upstream region of the gene. Transcriptional silencing of the Ehap-a gene continued even after the removal of the plasmid and the cloned amoebae were termed G3. Transfection of G3 trophozoites with a plasmid construct containing the cysteine proteinase (EhCP-5) gene and the light subunit of the Gal-lectin (Ehlgl1) gene, each under the 5' upstream sequences of the amoebapore gene, caused the simultaneous epigenetic silencing of expression of these two genes. The resulting trophozoites, termed RB-9, were cured from the plasmid and they do not express the three types of virulent genes. The RB-9 amoeba are virulence attenuated and are incapable of killing mammalian cells, they can not induce the formation of liver abscesses and they do not cause ulcerations in the cecum of experimental animals. The gene-silenced amoebae express the same surface antigens which are present in virulent strains and following intra peritoneal inoculation of live trophozoites into hamsters they evoked a protective immune response. Further studies are needed to find out if RB-9 trophozoites could be used for vaccination against amoebaisis.KEY WORDS : Entamoeba histolytica, RB-9 trophozoite, virulence.

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Cysteine Proteinases and the Pathogenesis of Amebiasis

Cited by 206 publications

References 121 publications

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

A Retromerlike Complex Is a Novel Rab7 Effector That Is Involved in the Transport of the Virulence Factor Cysteine Protease in the Enteric Protozoan ParasiteEntamoeba histolytica

Trophozoites ofEntamoeba histolyticaepigenetically silenced in several genes are virulence-attenuated

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