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A novel and divergent role of granzyme A and B in resistance to helminth infection

ABSTRACT: Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens and induce cytokines. Moreover, macrophages, T helper 2 cells, regulatory T cells, mast cells and B cells can express gzms. We recently reported gzm induction in human filarial infection. Here we show that in rodent filarial infection with Litomosoides sigmodontis worm loads were significantly reduced in gzmAxB and gzmB knock out (ko) mice, but enhanced in gzmA ko compared to wildtype (wt) mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and antibody shift and enhanced early inflammation gene expression, whereas gzmA deficiency was linked with alternatively activated macrophages and reduced inflammation. This suggests a novel and divergent role for gzms in helminth infection with gzmA contributing to resistance and gzmB promoting susceptibility. Keywords: knock out vs wild type

ORGANISM(S): Mus musculus

PROVIDER: GSE17544 | GEO | 2011/07/29

SECONDARY ACCESSION(S): PRJNA118539

REPOSITORIES: GEO

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Project description:Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of approximately 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 because the human-parasitic species cannot 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. 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 first-stage larvae (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 uncharacterised members of the transthyretin-like protein family. Furthermore, biotin labelling revealed that redox proteins and enzymes involved in purinergic signalling 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.

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A novel and divergent role of granzyme A and B in resistance to helminth infection

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