Dominant T‐cell epitopes of filarial BmALT‐2 and their cytokine profile in BALB/c mice

Madhumathi, Jayaprakasam; Prince, Prabhu Rajaiah; Rao, Dandina N.; Kaliraj, Perumal

doi:10.1111/j.1365-3024.2010.01239.x

Cited by 15 publications

(22 citation statements)

References 14 publications

(20 reference statements)

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“…The pathologic progression of this disease is intriguing and gruesome making it a difficult task to develop a vaccine against this multicellular parasite. Of the different vaccine candidates identified for lymphatic filariasis, the ALT-2 protein stands out as a remarkable one with no known homologue in mammalian hosts, imparting about 74% protection in jirds [13][14][15][16][17][18][19][20][21][22]. This study will lead to the development of commercial largescale production of BmALT-2 as an inexpensive vaccine candidate.…”

Section: Resultsmentioning

confidence: 99%

“…ALT-2 plays a role in the evasion strategy of the filarial nematodes by amplifying Th2 responses along with interfering signals necessary for the development of pro-inflammatory Th1 populations [12,15]. Earlier studies proposed BmALT-2 of B. malayi as a promising vaccine candidate with about 76% protection in animal models [12,[15][16][17][18][19][20][21][22]. Therefore, ALT-2 is considered the most potential vaccine candidate for lymphatic filariasis.…”

Section: Introductionmentioning

confidence: 99%

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Cloning, expression and characterization of Brugia malayi abundant larval protein transcript-2 (BmALT-2) expressed in Pichia pastoris

Paul

Saha

Selvaraja

et al. 2016

Biotechnology & Biotechnological Equipment

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Besides mass drug administration, successful elimination of human lymphatic filariasis, a mosquitoborne tropical parasitic disease, requires developing other suitable prophylactic agents such as vaccines. The Brugia malayi abundant larval transcript-2 (BmALT-2) protein has been identified as one possible candidate. So far, it (E-ALT-2) has been expressed as a 24-kDa non-glycosylated protein in Escherichia coli. Easy and low-cost downstream purification of secreted BmALT-2 in Pichia pastoris may be a vital option to inexpensive large-scale production. This study focused on expression and molecular characterization of BmALT-2 (P-ALT-2) in P. pastoris. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis showed that some P. pastoris colonies produced 27 and 24 kDa bands and few colonies produced a 24-kDa band. Preliminary studies confirmed glycosylation of 27 kDa P-ALT-2. The ratio of glycosylated and non-glycosylated P-ALT-2 was 20:80-70:30 in various colonies. The maximum yield of glycosylated and non-glycosylated P-ALT-2 was measured as 7.99 § 1.12 and 9.18 § 1.35 mg L ¡1 compared to 6.5 § 1.2 mg L ¡1 of E-ALT-2 in shake flasks. Their overall expression was about 25% and 35% higher than that in E. coli. The glycosylated P-ALT-2 exhibited about 15% higher immunoreactivity with human endemic normal sera. The enhanced secreted production by P. pastoris may lead to cost-effective large-scale production of BmALT-2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cloning, expression and characterization of Brugia malayi abundant larval protein transcript-2 (BmALT-2) expressed in Pichia pastoris

Paul

Saha

Selvaraja

et al. 2016

Biotechnology & Biotechnological Equipment

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“…When DAG was added externally to ALT‐2, the Th1 response was more pronounced. However, when ALT‐2 was covalently lipid modified, it not only elicited Th2 immune response that is reflected by high antibody levels and the IL‐4, IL‐5 or IL‐10 cytokine levels comparable with that of ALT‐2 , but also stimulated Th1 cells and as in the case with other lipoproteins , Thl cytokines (IFN‐γ) were secreted. In Leishmaniasis, mice vaccinated with a lipid‐modified protein were associated with enhancement of antigen‐specific IFN‐γ production .…”

Section: Discussionmentioning

confidence: 98%

Bacterial lipid modification enhances immunoprophylaxis of filarial abundant larval transcript‐2 protein in Mastomys model

Sharmila

Christiana

Pote

et al. 2013

Parasite Immunology

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As in many other parasitic diseases, efficacious vaccine for lymphatic filariasis has been elusive for want of new approaches leaving billions of people either debilitated or at risk. With multiple B- and T-cell epitopes, the abundant larval transcript-2 (ALT-2) of the filarial worm, Brugia malayi, has been shown to be a promising immunoprophylactic target. To enhance its efficacy, it was lipid modified using our recently developed protein engineering tool, which then offered 30% more immunoprotection (49 vs. 79%) in Mastomys coucha model. Sustained high levels of IFN-γ (about 100 times) and high antibody titres (10-fold) elicited by lipid-modified ALT-2, as compared to the native form, indicated the maintenance of Th1/Th2 balance that is impaired in filariasis. Thus, this study provides the basis for developing efficacious vaccines for filariasis and other parasitic diseases by exploiting bacterial lipid modification.

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“…These results suggest that rBmALT-2 is able to create an environment conducive of combating the pancreatic islet damage by lowering the inflammatory potential and by inducing generalized TH2 shift with characteristic cytokine and antibody responses. This larval transcript protein of filarial parasites as such is known for its potential to shift the immune response towards an apparent TH-2 bias [16]. Hence, it is quite comprehensible that the prevention of the profound TH-1 response Levels of IL-10, IL-4, TNF-a and IFN-c cytokines measured by sandwich ELISA in the culture supernatants of splenocytes from the diabetic mice (treated with rBmALT-2) followed by re-stimulation with the same antigen.…”

Section: Discussionmentioning

confidence: 99%

“…B. malayi ALT proteins have also been shown to be involved in the upregulation of host's Th2 immune responses [15]. Some of the T cell epitopes of B. malayi ALT-2 could induce high levels of IL-10 secretion in BALB/c mice suggesting their possible involvement in immunomodulation within the host [16].…”

Section: Introductionmentioning

confidence: 99%

Filarial Abundant Larval Transcript Protein ALT-2: An Immunomodulatory Therapeutic Agent for Type 1 Diabetes

Reddy

Amdare

et al. 2016

Ind J Clin Biochem

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Type 1 diabetes (T1D) that accounts for about 5-10 % of all diabetes cases results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. It is characterized by severe inflammatory reaction mediated by pronounced T helper type-1 response. Parasitic infections having the ability to skew the host immune responses towards type-2 type as a part of their defense mechanism are able to induce protection against autoimmune diseases like T1D. Hence, the present study is undertaken to explore a recombinant abundant larval transcript protein of the human lymphatic filarial parasite Brugia malayi (rBmALT-2), a known anti-inflammatory molecule for its therapeutic effect on streptozotocin (STZ)-induced T1D in mice. The diabetic mice on treatment with rBmALT-2 showed a significant (p \ 0.0005) decrease in their fasting blood glucose levels. By the end of the second week after the initiation of treatment with the rBmALT-2, 28 % of the diabetic mice became normal and none of them were diabetic by the end of 5th week. The anti-diabetic effect of rBmALT-2 significantly correlated with the concomitant redressal of the pancreatic histopathological damage caused by STZ assault (rho = 0.87; p \ 0.0005).The sera of rBmALT-2 treated diabetic mice had increased levels of IgG1 antibodies associated with decreased IgG2a antibodies against the principal autoantigen insulin. The splenocyte proliferative response and the cytokine release in the treated mice showed marked bias against inflammation skewing the immune response to Th-2 type. From this study, it can be envisaged that that filarial proteins like rBmALT-2 with effective immunomodulatory activity and anti-diabetic effect are promising alternative therapeutic agents for T1D.

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Dominant T‐cell epitopes of filarial BmALT‐2 and their cytokine profile in BALB/c mice

Cited by 15 publications

References 14 publications

Cloning, expression and characterization of Brugia malayi abundant larval protein transcript-2 (BmALT-2) expressed in Pichia pastoris

Cloning, expression and characterization of Brugia malayi abundant larval protein transcript-2 (BmALT-2) expressed in Pichia pastoris

Bacterial lipid modification enhances immunoprophylaxis of filarial abundant larval transcript‐2 protein in Mastomys model

Filarial Abundant Larval Transcript Protein ALT-2: An Immunomodulatory Therapeutic Agent for Type 1 Diabetes

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