title: The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo.
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.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dominik
authors.initials: D
authors.lastname: Rückerl
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Harcus
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Janice
authors.initials: J
authors.lastname: Murray
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Webb
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Babayan
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Department of Parasitology, University of Indonesia, Jakarta, Indonesia.
authors.forename: Agnes
authors.initials: A
authors.lastname: Kurniawan
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D015153:Blotting, Western; D017178:Brugia malayi / Q000201:enzymology / Q000276:immunology / Q000472:pathogenicity*; D004605:Elephantiasis, Filarial / Q000201:enzymology* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005849:Gerbillinae; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008842:Microfilariae; D014305:Triose-Phosphate Isomerase / Q000378:metabolism*
chemical_list: D000909:Antibodies, Helminth; D057134:Antibodies, Neutralizing; D014305:Triose-Phosphate Isomerase