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Review
. 2006 May 31;36(6):723-33.
doi: 10.1016/j.ijpara.2006.02.011. Epub 2006 Mar 13.

New weapons in the war on worms: identification of putative mechanisms of immune-mediated expulsion of gastrointestinal nematodes

David Artis  1
Affiliations
Review

New weapons in the war on worms: identification of putative mechanisms of immune-mediated expulsion of gastrointestinal nematodes

David Artis. Int J Parasitol. .

Abstract

Parasitic nematode infections of humans and livestock continue to impose a significant public health and economic burden worldwide. Murine models of intestinal nematode infection have proved to be relevant and tractable systems to define the cellular and molecular basis of how the host immune system regulates resistance and susceptibility to infection. While susceptibility to chronic infection is propagated by T helper cell type 1 cytokine responses (characterised by production of IL-12, IL-18 and interferon-gamma), immunity to intestinal-dwelling adult nematode worms is critically dependent on a type 2 cytokine response (controlled by CD4+T helper type 2 cells that secrete the cytokines IL-4, IL-5, IL-9 and IL-13). However, the immune effector mechanisms elicited by type 2 cytokines in the gut microenvironment that precipitate worm expulsion have remained elusive. This review focuses on new studies that implicate host intestinal epithelial cells as one of the dominant immune effector cells against this group of pathogens. Specifically, three recently identified type 2 cytokine-dependent pathways that could offer insights into the mechanisms of expulsion of parasitic nematodes will be discussed: (i) the intelectins, a new family of galactose-binding lectins implicated in innate immunity, (ii) the resistin-like molecules, a family of small cysteine-rich proteins expressed by multiple cell types, and (iii) cytokine regulation of intestinal epithelial cell turnover. Identifying how the mammalian immune response fights gastrointestinal nematode infections is providing new insights into host protective immunity. Harnessing these discoveries, coupled with identifying what the targets of these responses are within parasitic nematodes, offers promise in the design of a new generation of anti-parasitic drugs and vaccines.

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Figures

Fig. 1
Fig. 1
Intelectins are expressed by intestinal goblet cells following Trichuris muris infection. Genetically resistant BALB/c mice were infected with 150 T. muris eggs and cecal RNA or histologic sections prepared from naïve or infected animals on day 18 p.i. as previously described (Artis et al., 2002, 2004a,b). (A) reverse transcription-PCR analysis demonstrated robust upregulation of intelectin-1 and intelectin-2 in infected animals (details of primer sequences and methodology can be found in (Pemberton et al., 2004a)). (B)-(D) Immunofluorescent staining of intelectins (staining red) in naive (B) or infected mice (C) and (D). Paraformaldehyde-fixed tissues were wax-embedded and 5 μm sections stained using a polyclonal rabbit anti-intelectin1/2 antibody (a gift from Hugh Miller, University of Edinburgh, UK) following standard immunofluoresecence protocols. Intelectins are expressed within exocrine vesicles of intestinal goblet cells (D). Epithelial cell nuclei are stained in blue with DAPI. Blocking peptide confirmed specificity of staining. Bar, 100 μm.
Fig. 2
Fig. 2
Resistin-like molecule (RELM)-β is expressed exclusively in intestinal goblet cells following T. muris infection. Genetically resistant BALB/c mice were infected with 150 T. muris eggs and histologic sections prepared from naïve or infected animals on day 18 p.i. as previously described (Artis et al., 2002, 2004a,b). Paraformaldehyde-fixed tissues were wax-embedded and 5 mm sections stained using a polyclonal rabbit anti-RELMβ antibody (Peprotech, USA) following standard immunofluoresecence protocols. (A) Immunofluorescent staining revealed that RELMβ (staining green) is localised to intestinal goblet cells. (B) RELMβ is expressed exclusively within exocrine vesicles of intestinal goblet cells. Epithelial cell nuclei are stained in blue with DAPI. Blocking peptide confirmed specificity of staining. Bar, 50 μm.
Fig. 3
Fig. 3
Ultrastructural analysis of the bacillary pores of T. muris. (A) SEM of T. muris entering host intestinal epithelial cells in infected mice. Bar, 100 μm. Genetically resistant BALB/c mice were infected with 150 T. muris eggs and tissue sections prepared from naïve or infected animals on day 14 p.i. as previously described (Artis et al., 2004a; Tilney et al., 2005). (B) Higher power analysis revealed the localisation of the bacillary pores to the ventral surface of the parasites (box). Bar, 10 μm. (C) TEM demonstrated that a subset of pores contains numerous dendritic processes (boxes) from adjoining adjacent nerve cells. T, tegument; P, pore opening, L, actin rich plical structures surrounding the pore opening. Bar, 1 μm. (Adapted, with permission, from Tilney et al., 2005.)
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