The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Hewitson, J. P., Rückerl, D., Harcus, Y., Murray, J., Webb, L. M., Babayan, S. A. , Allen, J. E., Kurniawan, A. and Maizels, R. M. (2014) The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo. PLoS Pathogens, 10(2), e1003930. (doi:10.1371/journal.ppat.1003930)

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Abstract

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Babayan, Dr Simon
Authors: Hewitson, J. P., Rückerl, D., Harcus, Y., Murray, J., Webb, L. M., Babayan, S. A., Allen, J. E., Kurniawan, A., and Maizels, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in PLoS Pathogens 10(2):e1003930
Publisher Policy:Reproduced under a Creative Commons License

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