The Secreted Triose Phosphate Isomerase of <i>Brugia malayi</i> Is Required to Sustain Microfilaria Production <i>In Vivo</i>

<div><p>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 <i>Brugia malay</i>i 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 <i>B. malayi</i> TPI, or mice with the homologous protein from the rodent filaria <i>Litomosoides sigmodontis</i>, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult <i>B. malayi</i> resulted in 60–70% reductions in microfilarial levels <i>in vivo</i> 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 <i>B. malayi</i> filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections.</p>