Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites

Abstract

The protective immune response that develops following infection with many tissue-dwelling intestinal nematode parasites is characterised by elevations in IL-4 and IL-13 and increased numbers of CD4+ T cells, granulocytes and macrophages. These cells accumulate at the site of infection and in many cases can mediate resistance to these large multicellular pathogens. Recent studies suggest novel potential mechanisms mediated by these immune cell populations through their differential activation and ability to stimulate production of novel effector molecules. These newly discovered protective mechanisms may provide novel strategies to develop immunotherapies and vaccines against this group of pathogens. In this review, we will examine recent studies elucidating mechanisms of host protection against three widely-used experimental murine models of tissue-dwelling intestinal nematode parasites: Heligmosomoides polygyrus, Trichuris muris and Trichinella spiralis.

Fig. 1

Th1- and Th2-type granulomas have distinct cell types and phenotypes. (A) At day 4 after primary inoculation with Heligmosomoides polygyrus, the tissue-dwelling larva is surrounded by a neutrophilic infiltrate and macrophages. Th2 cells are not found at this early timepoint. (B) At day 4 after secondary challenge, the H. polygyrus larva provokes a Th2-type granuloma, characterized by Th2 cells, more eosinophils, and alternatively activated macrophages (AAMacs). (C) The response to Mycobacterium tuberculosis is typical of a Th1-type granuloma. Th1-derived IFN-γ results in classically activated macrophages, which use inducible nitric oxide synthase (iNOS) to generate microbicidal products that destroy phagocytosed bacteria.

Fig. 1

Th1- and Th2-type granulomas have distinct cell types and phenotypes. (A) At day 4 after primary inoculation with Heligmosomoides polygyrus, the tissue-dwelling larva is surrounded by a neutrophilic infiltrate and macrophages. Th2 cells are not found at this early timepoint. (B) At day 4 after secondary challenge, the H. polygyrus larva provokes a Th2-type granuloma, characterized by Th2 cells, more eosinophils, and alternatively activated macrophages (AAMacs). (C) The response to Mycobacterium tuberculosis is typical of a Th1-type granuloma. Th1-derived IFN-γ results in classically activated macrophages, which use inducible nitric oxide synthase (iNOS) to generate microbicidal products that destroy phagocytosed bacteria.

Fig. 1

Th1- and Th2-type granulomas have distinct cell types and phenotypes. (A) At day 4 after primary inoculation with Heligmosomoides polygyrus, the tissue-dwelling larva is surrounded by a neutrophilic infiltrate and macrophages. Th2 cells are not found at this early timepoint. (B) At day 4 after secondary challenge, the H. polygyrus larva provokes a Th2-type granuloma, characterized by Th2 cells, more eosinophils, and alternatively activated macrophages (AAMacs). (C) The response to Mycobacterium tuberculosis is typical of a Th1-type granuloma. Th1-derived IFN-γ results in classically activated macrophages, which use inducible nitric oxide synthase (iNOS) to generate microbicidal products that destroy phagocytosed bacteria.

Fig. 2

Different components of the Th2-type response are effective against different helminthic parasites. Responses involve Th2 cells (dark green), neutrophils (light blue), macrophages (dark blue), alternatively activated macrophages (AAMacs; red), eosinophils (purple), goblet cells (light green), epithelial cells (pink), epithelial syncytium (maroon), mast cells (orange) and secreted factors. (A) The localized memory response to the Heligmosomoides polygyrus tissue-dwelling larva is characterized by AAMacs. AAMac-mediated protection is arginase-dependent and includes secretion of the chitinase-like protein Ym-1 and resistin-like molecule α (RELMα). (B) An IL-13-dependent “epithelial escalator” uses increased cell turnover to displace the burrowing head of Trichuris muris. Epithelial cell thymic stromal lymphopoietin (TSLP) may stimulate Th2 responses and inhibit Th1-type inflammatory responses, and goblet cell resistin-like molecule β (RELMβ) may bind the worm. Eosinophils accumulate in the lamina propria but are not required for parasite expulsion. (C) Th2 cytokines induce mast cell protease 1 (mMCP-1) which disrupts epithelial cell tight junctions, and goblet cell hyperplasia, together creating a “leaky” gut environment that favors expulsion of Trichinella spiralis from the syncytium of epithelial cells where it rapidly matures and reproduces.

Fig. 2

Different components of the Th2-type response are effective against different helminthic parasites. Responses involve Th2 cells (dark green), neutrophils (light blue), macrophages (dark blue), alternatively activated macrophages (AAMacs; red), eosinophils (purple), goblet cells (light green), epithelial cells (pink), epithelial syncytium (maroon), mast cells (orange) and secreted factors. (A) The localized memory response to the Heligmosomoides polygyrus tissue-dwelling larva is characterized by AAMacs. AAMac-mediated protection is arginase-dependent and includes secretion of the chitinase-like protein Ym-1 and resistin-like molecule α (RELMα). (B) An IL-13-dependent “epithelial escalator” uses increased cell turnover to displace the burrowing head of Trichuris muris. Epithelial cell thymic stromal lymphopoietin (TSLP) may stimulate Th2 responses and inhibit Th1-type inflammatory responses, and goblet cell resistin-like molecule β (RELMβ) may bind the worm. Eosinophils accumulate in the lamina propria but are not required for parasite expulsion. (C) Th2 cytokines induce mast cell protease 1 (mMCP-1) which disrupts epithelial cell tight junctions, and goblet cell hyperplasia, together creating a “leaky” gut environment that favors expulsion of Trichinella spiralis from the syncytium of epithelial cells where it rapidly matures and reproduces.

Fig. 2

Different components of the Th2-type response are effective against different helminthic parasites. Responses involve Th2 cells (dark green), neutrophils (light blue), macrophages (dark blue), alternatively activated macrophages (AAMacs; red), eosinophils (purple), goblet cells (light green), epithelial cells (pink), epithelial syncytium (maroon), mast cells (orange) and secreted factors. (A) The localized memory response to the Heligmosomoides polygyrus tissue-dwelling larva is characterized by AAMacs. AAMac-mediated protection is arginase-dependent and includes secretion of the chitinase-like protein Ym-1 and resistin-like molecule α (RELMα). (B) An IL-13-dependent “epithelial escalator” uses increased cell turnover to displace the burrowing head of Trichuris muris. Epithelial cell thymic stromal lymphopoietin (TSLP) may stimulate Th2 responses and inhibit Th1-type inflammatory responses, and goblet cell resistin-like molecule β (RELMβ) may bind the worm. Eosinophils accumulate in the lamina propria but are not required for parasite expulsion. (C) Th2 cytokines induce mast cell protease 1 (mMCP-1) which disrupts epithelial cell tight junctions, and goblet cell hyperplasia, together creating a “leaky” gut environment that favors expulsion of Trichinella spiralis from the syncytium of epithelial cells where it rapidly matures and reproduces.