Neospora caninum protein disulfide isomerase is involved in tachyzoite-host cell interaction

Naguleswaran, Arunasalam; Alaeddine, Ferial; Guionaud, Christophe; Vonlaufen, Nathalie; Sonda, Sabrina; Jenoe, Paul; Mevissen, Meike; Hemphill, Andrew

doi:10.1016/j.ijpara.2005.06.006

Cited by 47 publications

(44 citation statements)

References 54 publications

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“…In vitro studies on Neospora have shown that the enzyme activity of recombinant NcPDI is inhibited by NTZ and other nitro and non-nitrothiazolides that also inhibit parasite proliferation. Inhibition of NcPDI could result in an impairment of its functions, leading to protein misfolding followed by an impaired metabolic activity (Naguleswaran, 2005;Müller 2007). …”

Section: Mode Of Action Of Thiazolides On Intracellular Protozoamentioning

confidence: 99%

Drug treatment and novel drug target againstCryptosporidium

Gargala

2008

Parasite

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Summary :Cryptosporidiosis emergence triggered the screening of many compounds for potential anti-cryptosporidial activity in which the majority were ineffective. The outbreak of cryptosporidiosis which occurred in Milwaukee in 1993 was not only the first significant emergence of Cryptosporidium spp. as a major human pathogen but also a huge waterborne outbreak thickening thousands of people from a major city in North America. Since then, outbreaks of cryptosporidiosis are regularly occurring throughout the world. New drugs against this parasite became consequently urgently needed. Among the most commonly used treatments against cryptosporidiosis are paromomycin, and azithromycin, which are partially effective. Nitazoxanide (NTZ)'s effectiveness was demonstrated in vitro, and in vivo using several animal models and finally in clinical trials. It significantly shortened the duration of diarrhea and decreased mortality in adults and in malnourished children. NTZ is not effective without an appropriate immune response. In AIDS patients, combination therapy restoring immunity along with antimicrobial treatment of Cryptosporidium infection is necessary. Recent investigations focused on the potential of molecular-based immunotherapy against this parasite. Others tested the effects of probiotic bacteria, but were unable to demonstrate eradication of C. parvum. New synthetic isoflavone derivatives demonstrated excellent activity against C. parvum in vitro and in a gerbil model of infection. Newly synthesized nitroor non nitro-thiazolide compounds, derived from NTZ, have been recently shown to be at least as effective as NTZ against C. parvum in vitro development and are promising new therapeutic agents.

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Section: Mode Of Action Of Thiazolides On Intracellular Protozoamentioning

confidence: 99%

Drug treatment and novel drug target againstCryptosporidium

Gargala

2008

Parasite

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“…Moreover, it has recently been shown that native PDI on the cell surface is required for the effective attachment of Chlamydia, an obligate intracellular bacterial pathogen of eukaryotic cells (Conant and Stephens 2007). Likewise, a 52-kDa PDI of N. caninum techyzoites is involved in the adhesion of parasites to host cells (Naguleswaran et al 2005). The detection of anti-PDI IgA in tears of bovines infected with N. caninum suggests that PDIspecific antibodies may constitute part of the mucosal antibody repertoire, which is possibly involved in defense against protozoan parasites (Liao et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Identification and enzymatic activities of four protein disulfide isomerase (PDI) isoforms of Leishmania amazonensis

Hong

Soong

2007

Parasitol Res

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Leishmania parasites primarily infect cells of macrophage lineage and can cause leishmaniasis in the skin, mucosal, and visceral organs, depending on both host-and parasite-derived factors. The protein disulfide isomerases (PDIs) are thiol-disulfide oxidoreductases that catalyze the formation, reduction, and isomerization of disulfide bonds of proteins in cells. Although four Leishmania PDI genes are functionally inferred from homology in the genome sequences, only two of them have been expressed as active proteins to date. The functional relationship among various PDI enzymes remains largely unclear. In this study, we expressed and partially characterized all four L. amazonensis PDIs encoding 52-, 47-, 40-, and 15-kDa proteins. Homology analysis showed that the sequence identity between L. amazonensis (New World) PDIs and their counterpart PDI sequences from L. major (Old World) ranged from 76% to 99%. Kinetic characterization indicated that while the 15-, 40-, and 47-kDa PDI proteins displayed both insulin isomerase and reductase activities, the 52-kDa protein had only isomerase activity with no detectable reductase activity. All four PDI proteins were recognized by sera from L. amazonensis-infected mice and were sensitive to inhibition by standard PDI inhibitors. This study describes the enzymatic activities of recombinant L. amazonensis PDIs and suggests a role for these proteins in parasite development.

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“…Toxoplasma is suggested to tightly regulate ER homeostatic pathways to allow for the production of properly folded secretory proteins required for host cell adhesion and invasion, evasion of the host response, and conversion from a highly invasive and actively proliferating form (tachyzoite) to a latent cyst (bradyzoite) (5). These processes are central for parasite viability, and as a result, pharmacological agents that alter homeostasis within the ER are detrimental to apicomplexan parasites (6)(7)(8)(9).…”

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The Unfolded Protein Response in the Protozoan Parasite Toxoplasma gondii Features Translational and Transcriptional Control

et al. 2013

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The unfolded protein response (UPR) is an important regulatory network that responds to perturbations in protein homeostasis in the endoplasmic reticulum (ER). In mammalian cells, the UPR features translational and transcriptional mechanisms of gene expression aimed at restoring proteostatic control. A central feature of the UPR is phosphorylation of the ␣ subunit of eukaryotic initiation factor-2 (eIF2) by PERK (EIF2AK3/PEK), which reduces the influx of nascent proteins into the ER by lowering global protein synthesis, coincident with preferential translation of key transcription activators of genes that function to expand the processing capacity of this secretory organelle. Upon ER stress, the apicomplexan parasite Toxoplasma gondii is known to induce phosphorylation of Toxoplasma eIF2␣ and lower translation initiation. To characterize the nature of the ensuing UPR in this parasite, we carried out microarray analyses to measure the changes in the transcriptome and in translational control during ER stress. We determined that a collection of transcripts linked with the secretory process are induced in response to ER stress, supporting the idea that a transcriptional induction phase of the UPR occurs in Toxoplasma. Furthermore, we determined that about 500 gene transcripts showed enhanced association with translating ribosomes during ER stress. Many of these target genes are suggested to be involved in gene expression, including JmjC5, which continues to be actively translated during ER stress. This study indicates that Toxoplasma triggers a UPR during ER stress that features both translational and transcriptional regulatory mechanisms, which is likely to be important for parasite invasion and development.

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Neospora caninum protein disulfide isomerase is involved in tachyzoite-host cell interaction

Cited by 47 publications

References 54 publications

Drug treatment and novel drug target againstCryptosporidium

Drug treatment and novel drug target againstCryptosporidium

Identification and enzymatic activities of four protein disulfide isomerase (PDI) isoforms of Leishmania amazonensis

The Unfolded Protein Response in the Protozoan Parasite Toxoplasma gondii Features Translational and Transcriptional Control

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