Abstract
BackgroundFilarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.Methodology and Principal FindingsWe immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.ConclusionsWe have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.
Highlights
DNA vaccination is a promising technology that is being developed to combat diseases such as flu, HIV, and cancer [1]
We have developed a successful strategy for DNA vaccination against a nematode infection that targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells
PCR products of genes of interest were digested with NotI and XbaI (Neb laboratory, UK), ligated into an NotI and XbaI-digested anti-mouse dec-205 single chain antibody ovalbumin construct (DEC-OVA) or antibody control Ig-OVA to replace the fragment of OVA gene, respectively
Summary
DNA vaccination is a promising technology that is being developed to combat diseases such as flu, HIV, and cancer [1]. Control programs in some areas are threatened by the emergence of drug-resistance [2,3], while in communities where both onchocerciasis and loiasis are endemic, mass treatment with ivermectin is contraindicated because of the risk of severe side effects associated with death of Loa loa microfilariae [4] These circumstances argue strongly for the development of vaccines to complement drug treatment strategies. Given that the maintenance and transmission of filarial infections requires very few adult parasites [11] and that our previous work suggests that they are able to increase their fecundity in response to host immune attack [12], any intervention strategy should be assessed by its ability to suppress the transmissible stages, the microfilariae Is this critical to reducing disease transmission, but in onchocerciasis microfilariae are the main cause of pathology. The efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation
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