Browsing by Author "Ariyaratne, Anupama"

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    Characterizing Host Protective Immune Responses to the Parasitic Worm Heligmosomoides polygyrus
    (2020-05-05) Ariyaratne, Anupama; Finney, Constance A. M.; Hirota, Simon Andrew; Storey, Douglas G.
    Intestinal roundworms cause chronic debilitating disease in humans and livestock. The lack of vaccines and the emerging drug resistance only increase the need to better understand worm-host interactions. H. polygyrus larvae induce an intestinal granuloma response whereby immune cells, mostly alternatively activated macrophages and eosinophils, accumulate around the tissue encysted parasites. In vitro, these cells and antibodies immobilize, damage/kill worms within the granuloma. This is yet to be confirmed in vivo. We focused on understanding: the mechanisms underlying effective granulomas (chapter 1), the role of resistin like molecule (RELM) alpha, a protein shown to downregulate Th2 immunity (chapter 2), and eosinophils, an enigmatic cell type whose role in anti-worm immunity remains controversial (chapter 3). C57Bl/6 mice are susceptible to H. polygyrus infection. However, mice that are infected using a more natural approach (multiple low doses – (trickle) - as opposed to one large dose (bolus)), had fewer adult worms with more granulomas. Their granulomas had decreased RELM- expression, increased anti-parasitic RELM- and fibrotic gene expression as well as a stronger IgG1 accumulation. In the absence of RELM-, granulomas from trickle-infected mice remained more protective, with upregulated genes involved in eosinophil chemotaxis. Despite this increased eosinophil recruitment, the granulomas from RELM--/- mice were not as protective as those from wild type animals highlighting the need for RELM- for maximal granuloma efficiency. In WT mice, we found eosinophils accumulated around tissue encysted H. polygyrus during acute and chronic infections. The spleen, mesenteric lymph nodes and Peyer’s patches (PP) had increased eosinophilia, with resident and recruited eosinophil surface markers. In addition, eosinophils accumulated around the protozoan parasite Toxoplasma gondii indicating that intestinal eosinophils may represent a key cell type in immunity to different types of incoming parasites. T. gondii infection did not increase eosinophil numbers in the intestine or PP. However, eosinophils showed an inflammatory phenotype marked by increased MHC II and CD101 expression. These findings highlight that the granuloma is a key, complex site of anti-worm immunity and that trickle infection models provide us with a novel tool to study the mechanisms at play within granulomas.