Journal
PLOS PATHOGENS
Volume 10, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1003930
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Funding
- Wellcome Trust [090281]
- Medical Research Council UK studentship
- EU [242131]
- Medical Research Council UK [G0600818]
- MRC [G0600818] Funding Source: UKRI
- Medical Research Council [G0600818] Funding Source: researchfish
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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 IFN 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. Author Summary Triose phosphate isomerase (TPI) is a ubiquitous and highly conserved enzyme in intracellular glucose metabolism. Surprisingly, the human lymphatic filariai nematode parasite Brugia malayi, releases TPI into the extracellular environment, suggesting a role in helminth survival in the mammalian host. We first established that B. malayi-infected humans and rodents generate TPI-specific serum antibody responses, confirming presentation of this protein to the host immune system. However, immunisation of rodents with B. malayi TPI did not induce protection against infection. Furthermore, TPI from a related parasite, Litomosoides sigmodontis, did not induce protective immunity in mice. Notably, antibodies from infected hosts did not neutralise the enzymatic activity of TPI. We then generated twenty-three anti-TPI monoclonal antibodies, of which only two inhibited enzymatic activity. Transfer of neutralising antibody to mice prior to B. malayi infection effected a 69.5% reduction in microfilarial levels in vivo and a 60% reduction in microfilariae produced by individual adult female parasites. Corresponding shifts in the host immune response included reduced Th1 cytokine production and enhanced macrophage numbers. Enzymatically active TPI therefore promotes production of the transmission stage of B. malayi filarial parasites and represents a rational target for new vaccine and drug development to protect against filarial infections.
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