title: Comparative analysis of the secretome from a model filarial nematode (Litomosoides sigmodontis) reveals maximal diversity in gravid female parasites.
abstract: Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of ∼6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been constrained by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model, as BALB/c mice are fully permissive for its development and reproduction. Here, we provide a comprehensive analysis of excretory-secretory products from L. sigmodontis across five lifecycle stages and identifications of host proteins associated with first-stage larvae (microfilariae) in the blood. Applying intensity-based quantification, we determined the abundance of 302 unique excretory-secretory proteins, of which 64.6% were present in quantifiable amounts only from gravid adult female nematodes. This lifecycle stage, together with immature microfilariae, released four proteins that have not previously been evaluated as vaccine candidates: a predicted 28.5 kDa filaria-specific protein, a zonadhesin and SCO-spondin-like protein, a vitellogenin, and a protein containing six metridin-like ShK toxin domains. Female nematodes also released two proteins derived from the obligate Wolbachia symbiont. Notably, excretory-secretory products from all parasite stages contained several uncharacterized members of the transthyretin-like protein family. Furthermore, biotin labeling revealed that redox proteins and enzymes involved in purinergic signaling were enriched on the adult nematode cuticle. Comparison of the L. sigmodontis adult secretome with that of the human-infective filarial nematode Brugia malayi (reported previously in three independent published studies) identified differences that suggest a considerable underlying diversity of potential immunomodulators. The molecules identified in L. sigmodontis excretory-secretory products show promise not only for vaccination against filarial infections, but for the amelioration of allergy and autoimmune diseases.
authors: From the ‡Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK;
authors: Stuart D
authors: SD
authors: Armstrong
authors: §Centre for Immunity, Infection & Evolution and Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK;
authors: Simon A
authors: SA
authors: Babayan
authors: ¶UMR 7245 MCAM CNRS, Muséum National d'Histoire Naturelle, 75231 Paris, France;
authors: Nathaly
authors: N
authors: Lhermitte-Vallarino
authors: §Centre for Immunity, Infection & Evolution and Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK;
authors: Nick
authors: N
authors: Gray
authors: From the ‡Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK;
authors: Dong
authors: D
authors: Xia
authors: ¶UMR 7245 MCAM CNRS, Muséum National d'Histoire Naturelle, 75231 Paris, France;
authors: Coralie
authors: C
authors: Martin
authors: §Centre for Immunity, Infection & Evolution and Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK;
authors: Sujai
authors: S
authors: Kumar
authors: ‖Division of Pathway Medicine, University of Edinburgh, Edinburgh EH9 3JT, UK;
authors: David W
authors: DW
authors: Taylor
authors: §Centre for Immunity, Infection & Evolution and Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK;
authors: Mark L
authors: ML
authors: Blaxter
authors: From the ‡Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK; **The National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool L3 5RF, UK.
authors: Jonathan M
authors: JM
authors: Wastling
authors: From the ‡Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK; blm1@liverpool.ac.uk.
authors: Benjamin L
authors: BL
authors: Makepeace
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005368:Filariasis / Q000097:blood / Q000469:parasitology*; D005370:Filarioidea / Q000145:classification / Q000254:growth & development* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D015801:Helminth Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D040901:Proteomics / Q000379:methods*; D012737:Sex Factors
chemical_list: D015801:Helminth Proteins