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

Abstract

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.

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

“…Irradiated larvae (46,114,129,131), dead larvae (117), the soluble fraction of larvae (117), live MF (117,132), killed MF (46), MF antigen (46,133), and SDS extracts of adults (134) were all protective against L3 infection, even though many of these antigen preparations contained no adjuvant. Specific antigens that have been tried in this model include abundant larval transcript (135,136), thioredoxin peroxidase (135), transglutaminase (137), Bm97 (138), HSP12.6␣c (139), and paramyosin (138), all of which have been shown to be at least partially protective.…”

Improving the efficacy of a prophylactic vaccine formulation against lymphatic filariasis

“…Our laboratory and others have identified several potential vaccine antigens that are shown to confer significant protection against challenge infections in experimental animals (Samykutty et al 2010; Dakshinamoorthy et al 2013b, Dakshinamoorthy et al 2013c; Arumugam et al 2014). One of our recent trials in non-human primates using a trivalent fusion protein vaccine (r Bm HAT) showed that approximately 40% protection could be achieved in vaccinated animals against a challenge infection (Dakshinamoorthy et al 2012). In these studies we used alum as an adjuvant and the immune responses were predominantly biased towards IgG1/IL-4.…”

Recent Advances in Elucidating Nematode Moulting – Prospects of Using Oesophagostomum dentatum as a Model

“…API, CUT-1, HSP-12.6, HSP-60, HSP-70 and TTL-5) might serve as potential vaccine candidates, as nematodes exploit heat shock proteins (including HSP-12.6, HSP-60 and HSP-70) to modulate or suppress the host's immune responses and support parasite survival (cf. Dakshinamoorthy et al, 2012;Shiny et al, 2011;Wang et al, 2009). Moreover, the antigenic nematode-specific proteins API, CUT-1 and TTL-5 lack homology to mammalian host proteins and are unlikely to have adverse effects on mammals, and thus might represent promising immunogens.…”