Abstract
Human lymphatic filariasis, a mosquito-borne neglected tropical parasitic disease, needs an early development of prophylactic agents such as a vaccine for its successful elimination. Our earlier study suggested the enhanced immunological response by fusion protein (P-TUFT-ALT-2) of Tuftsin and ALT-2 in a mice model. We cultured human peripheral blood mononuclear cells (PBMCs) and treated cells with Escherichia coli-expressed ALT-2 (E-ALT-2) and P-TUFT-ALT-2. Real-time polymerase chain reaction was performed to identify the mRNA copy number of various cytokine and transcription factor genes. The recombinant vaccine candidate was also validated for humans by immunoreactivity with human sera samples of natural infection. In this study, P-TUFT-ALT-2 stimulated 12% higher PBMC proliferation in endemic normal (EN) individuals than E-ALT-2 alone. There was enhanced production of IFN γ, IL-2, IL-5 and IL-12, indicating a balanced Th1/Th2 response. However, higher expression of IL-5 and lower IL-4 validate the humoral response through an IL-5-dependent manner. Also, high level of IL-17 indicates a strong Th/Treg regulation over T-cell activation. The upregulated T-bet might have enhanced IFN-γ production, whereas GATA-3 was supposed to enhance IL-5 expression. The fusion protein also exhibited 15–16% higher reactivity with EN clinical sera, exposing the upregulation of IgG1 and IgM in natural infection. The higher reactivity of P-TUFT-ALT-2 with sera of natural infection (EN) was validated indirectly by B-cell activation through various cytokines and regulatory genes produced from different T cells. Thus, these findings endorse P-TUFT-ALT-2 as a potential vaccine candidate for human lymphatic filariasis.
Highlights
Lymphatic filariasis is a mosquito-borne parasitic disease caused mainly by Wuchereria bancrofti and Brugia malayi
The IL-2 and IFN-γ levels were high in the cultures stimulated with P-TUFT-ALT-2 (3.88- and 7.89-fold) and expressed ALT-2 (E-ALT-2) (3.64- and 8.22-fold)
The mRNA fold numbers of IL-5, IL-12 and IL-17 were significantly higher in P-TUFT-ALT-2-induced Peripheral blood mononuclear cells (PBMCs) (6.96, 1.35- and 8.60-fold, respectively) than in the E-ALT-2-induced culture (5.56, 0.09- and 0.62-fold, respectively)
Summary
Lymphatic filariasis is a mosquito-borne parasitic disease caused mainly by Wuchereria bancrofti and Brugia malayi. The filarial parasites have already caused lymphatic filariasis in 947 million people of 54 countries, with over 36 million critically disfigured [1]. About 57% of the world’s population faces the risk of infection with lymphatic filarial parasites in tropical regions of southeast Asia (nine countries), and about 37% of these people live in the African region (35 countries). The World Health Organization has already initiated a Global Program to Eliminate Lymphatic Filariasis (GPELF) by the year 2020 with mass drug administration using diethylcarbamazine or ivermectin combined with albendazole [4,5,6]. Anti-parasitic drugs are successful to control parasitic diseases These have only microfilaricidal effect without any impact on the larval or adult worms even after prolonged application. People infected with B. malayi show a high frequency of IgG1 and IgG3 antibodies to ALT-2 [17]
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