Characterization of human immune responses to the cytosolic superoxide dismutase and glutathione S‐transferase from <i>Onchocerca volvulus</i>

Nw, Brattig; Kh, Henkle-Dührsen; S, Hounkpatin; Liebau, Eva; Tf, Kruppa; Pf, Zipfel

doi:10.1046/j.1365-3156.1997.d01-384.x

Cited by 12 publications

(9 citation statements)

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“…The resulting antibody profile is characteristic of the varying forms of onchocerciasis that reflect different immune states. In the present study, OvGST3 was shown to be an antigen of low immunogenicity, comparable to the results obtained for other enzymatic antioxidants from O. volvulus such as the superoxide dismutase 1 (OvSOD1) or the OvGST2 [37].…”

Section: Protein Sequence Analysissupporting

confidence: 87%

The secretory omega‐class glutathione transferase OvGST3 from the human pathogenic parasite Onchocerca volvulus

et al. 2008

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The glutathione S-transferases (GSTs) constitute a highly versatile superfamily that is thought to have evolved from a thioredoxin-like ancestor in response to the development of oxidative stress, sharing sequence and structural similarities with several stress-related proteins in a widespread range of organisms. Additionally, several GST-related proteins have been described, demonstrating that this ancient protein fold has been 'recycled' by nature for new functions, such as plant stress-induced proteins, bacterial stringent starvation Onchocerciasis or river blindness, caused by the filarial nematode Onchocerca volvulus, is the second leading cause of blindness due to infectious diseases. The protective role of the omega-class glutathione transferase 3 from O. volvulus (OvGST3) against intracellular and environmental reactive oxygen species has been described previously. In the present study, we continue our investigation of the highly stress-responsive OvGST3. Alternative splicing of two exons and one intron retention generates five different transcript isoforms that possess a spliced leader at their 5¢-end, indicating that the mechanism of mature mRNA production involves alternative-, cis-and trans-splicing processes. Interestingly, the first two exons of the ovgst3 gene encode a signal peptide before sequence identity to other omega-class glutathione transferases begins. Only the recombinant expression of the isoform that encodes the longest deduced amino acid sequence (OvGST3 ⁄ 5) was successful, with the purified enzyme displaying modest thiol oxidoreductase activity. Significant IgG1 and IgG4 responses against recombinantly expressed OvGST3 ⁄ 5 were detected in sera from patients with the generalized as well as the chronic hyperreactive form of onchocerciasis, indicating exposure of the secreted protein to the human host's immune system and its immunogenicity. Immunohistological localization studies performed at light and electron microscopy levels support the extracellular localization of the protein. Intensive labeling of the OvGST3 was observed in the egg shell at the morula stage of the embryo, indicating extremely defined, stage-specific expression for a short transient period only.

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Section: Protein Sequence Analysissupporting

confidence: 87%

The secretory omega‐class glutathione transferase OvGST3 from the human pathogenic parasite Onchocerca volvulus

et al. 2008

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“…In another study also we observed a similar Th2 biased responses following immunization of mice with OvGST-2 of O. volvulus [29] or rBmALT of B. malayi . In these studies also EN individuals were the only one showing predominantly IgG1 and IgG3 antibody responses [30],[31]. Another interesting observation in the present study was that MF individuals carry IgG2 antibodies against WbGST in their sera suggesting largely a Th1 type response in these individuals compared to putatively resistant EN individuals who show a Th2 biased antibody responses in their sera.…”

Section: Discussionsupporting

confidence: 61%

Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis

et al. 2009

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BackgroundLymphatic filarial parasites survive within the lymphatic vessels for years despite the complex immune environment surrounding them. Parasites possibly accomplish this by adopting various immunomodulatory strategies, which include release of glutathione-S-transferases (GSTs) that counteract the oxidative free radicals produced by the host. Since GSTs produced by parasites appear to be critical for the survival of parasites in the host, several studies evaluated the potential of parasite GSTs as vaccine candidates especially against schistosomiasis, fascioliasis and Seteria cervi. However, vaccine potential of GSTs of lymphatic filarial parasites has not been evaluated before.Methods/Principal FindingsIn the present study, the GST gene was cloned from the third stage larval (L3) cDNA libraries of Wuchereria bancrofti, and recombinant GST (WbGST) was expressed and purified. Serum samples from individuals living in an endemic area were analyzed for their reactivity with rWbGST. These findings showed that sera from endemic normal individuals (EN) carry significant levels of anti-WbGST IgG antibodies compared to subjects who are microfilaraemic (Mf) or show symptoms of clinical pathology (CP). Isotype analysis of the anti-WbGST IgG antibodies showed a predominance of IgG1 and IgG3 antibodies in EN individuals. Subsequent functional analysis of the rWbGST showed that the rWbGST protein retained the enzymatic activity of GST and the antibodies in EN sera could inhibit this enzymatic activity. Similar results were obtained when anti-rWbGST antibodies raised in mice were used in the neutralization assay. Brugia malayi GST and WbGST show significant sequence similarity. Therefore, to evaluate the vaccine potential of rWbGST, we used B. malayi L3 as challenge parasites. Vaccine potential of rWbGST was initially evaluated by confirming the role of human and mice WbGST antibodies in an antibody dependent cellular cytotoxicity (ADCC) assay. Subsequent vaccination studies in a jird model showed that approximately 61% protection could be achieved against a B. malayi L3 challenge infection in jirds immunized with rWbGST.ConclusionsResults of this study show that rWbGST is a potential vaccine candidate against lymphatic filariasis. Nearly 61% protection can be achieved against a B. malayi challenge infection in a jird model. The study also showed that the WbGST protein retained the enzymatic activity of GST and this enzymatic activity appears to be critical for the survival of the parasite in the host.

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“…Anti-BmHsp12.6 and anti-BmHsp12.6αc peptide antibodies present in the sera of EN subjects were predominantly cryophilic IgG1 and IgG3 antibodies. Other studies have also reported similar antibody responses that are protective in EN subjects [3], [50]–[52].…”

Section: Discussionsupporting

confidence: 53%

Biochemical Characterization and Evaluation of a Brugia malayi Small Heat Shock Protein as a Vaccine against Lymphatic Filariasis

et al. 2012

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Filarial nematodes enjoy one of the longest life spans of any human pathogen due to effective immune evasion strategies developed by the parasite. Among the various immune evasion strategies exhibited by the parasite, Interleukin 10 (IL-10) productions and IL-10 mediated immune suppression has significant negative impact on the host immune system. Recently, we identified a small heat shock protein expressed by Brugia malayi (BmHsp12.6) that can bind to soluble human IL-10 receptor alpha (IL-10R) and activate IL-10 mediated effects in cell lines. In this study we show that the IL-10R binding region of BmHsp12.6 is localized to its N-terminal region. This region has significant sequence similarity to the receptor binding region of human IL-10. In vitro studies confirm that the N-terminal region of BmHsp12.6 (N-BmHsp12.6) has IL-10 like activity and the region containing the alpha crystalline domain and C-terminus of BmHsp12.6 (BmHsp12.6αc) has no IL-10 like activity. However, BmHsp12.6αc contains B cell, T cell and CTL epitopes. Members of the sHSP families are excellent vaccine candidates. Evaluation of sera samples from putatively immune endemic normal (EN) subjects showed IgG1 and IgG3 antibodies against BmHsp12.6αc and these antibodies were involved in the ADCC mediated protection. Subsequent vaccination trials with BmHsp12.6αc in a mouse model using a heterologous prime boost approach showed that 83% protection can be achieved against B. malayi L3 challenge. Results presented in this study thus show that the N-BmHsp12.6 subunit of BmHsp12.6 has immunoregulatory function, whereas, the BmHsp12.6αc subunit of BmHsp12.6 has significant vaccine potential.

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Characterization of human immune responses to the cytosolic superoxide dismutase and glutathione S‐transferase from Onchocerca volvulus

Cited by 12 publications

References 40 publications

The secretory omega‐class glutathione transferase OvGST3 from the human pathogenic parasite Onchocerca volvulus

The secretory omega‐class glutathione transferase OvGST3 from the human pathogenic parasite Onchocerca volvulus

Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis

Biochemical Characterization and Evaluation of a Brugia malayi Small Heat Shock Protein as a Vaccine against Lymphatic Filariasis

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