Worm Expulsion In Mice Research Articles

IL-4/IL-13-producing ILC2s are required for timely control of intestinal helminth infection in mice.

Infection of mice with Nippostrongylus brasiliensis (Nb) serves as a model for human hookworm infection affecting about 600 million people world-wide. Expulsion of Nb from the intestine requires IL-13-mediated mucus secretion from goblet cells and activation of smooth muscles cells. Type 2 innate lymphoid cells (ILC2s) are a major cellular source of IL-13 but it remains unclear whether IL-13 secretion from ILC2s is required for Nb expulsion. Here, we compared the immune response to Nb infection in mixed bone marrow chimeras with wild-type or IL-4/IL-13-deficient ILC2s. ILC2-derived IL-4/IL-13 was required for recruitment of eosinophils to the lung but had no influence of systemic eosinophil levels. In the small intestine, goblet cell hyperplasia and tuft cell accumulation was largely dependent on IL-4/IL-13 secretion from ILC2s. This further translated to higher eggs counts and impaired worm expulsion in mice with IL-4/IL-13-deficient ILC2s. Overall, we demonstrate that ILC2s constitute a non-redundant source of IL-4/IL-13 required for protective immunity against primary Nb infection.

Disruption of Th2 Immunity Results in a Gender-Specific Expansion of IL-13 Producing Accessory NK Cells during Helminth Infection

Host gender has previously been identified as a determining factor in the resolution of Trichuris muris infection in mice lacking IL-4 (IL-4KO BALB/c). Worm expulsion in these mice is delayed, but occurs in females. In this study we were able to demonstrate delayed expulsion occurs at day 26 post infection and is associated with the production of the key Th2-associated cytokine IL-13 by both CD4(+) T cells and an auxiliary DX5(+) NK cell source, as well as a concurrent reduction in proinflammatory cytokines. NK cell number was comparably increased in both sexes, but NK cells from male mice were found to express higher levels of the chemokine receptor CXCR3. Depletion of CD4(+) T cells completely prevented parasite expulsion, whereas loss of NK cells resulted in a mild, but significant delay. Furthermore, IL-18 is a cytokine with the capacity to enhance both Th1 and Th2 responses found to be dispensable for worm expulsion in female mice but was a key factor for the suppression of the Th2 response in male IL-4KO mice. In contrast neutralization of IFN-gamma resulted in a complete restoration of typical wild-type BALB/c expulsion kinetics. This study sheds further light on the role of accessory NK cells in supplementing the IL-13-driven immune response when normal Th2 immunity is disrupted, and further identifies host gender as a key factor in determining the generation of "NK cell help".

Effect of oxygen radicals and differential expression of catalase and superoxide dismutase in adult Heligmosomoides polygyrus during primary infections in mice with differing response phenotypes.

The ability of oxygen radicals to kill Heligmosomoides polygyrus adult worms was examined by assessing parasite survival following incubation with hydrogen peroxide and acetaldehyde/xanthine oxidase, generators of H2O2 and H2O2/O2(-), respectively. H. polygyrus worms could tolerate levels of < 0.25 mM hydrogen peroxide and < 0.5 mM/20 mU acetaldehyde/xanthine oxidase for 20 h, but, at higher concentrations, marked sex-dependent susceptibility was observed, with males being more sensitive to H2O2 and O2(-) than female worms. The ability to evade free radical-mediated damage was also evaluated by measuring superoxide dismutase (SOD) and catalase levels in worms isolated at different time points from four strains of mice with differing resistance phenotypes. Levels of both catalase and SOD in female worms isolated from 'rapid'[(SWRxSJL)F1], 'fast' (SWR) or 'intermediate' (BALB/c), but not 'slow' (C57BL/10), responder mice showed a strain-dependent increase with time. Moreover, male worms were rejected faster than female worms in the 'rapid', 'fast' and 'intermediate' responder strains of mice. The results suggest that host-derived free radicals can damage adult worms and that female worms can increase production of their scavenging enzymes in response to the immune onslaught that eventually leads to worm expulsion in mice with 'fast', 'rapid' or 'intermediate' response phenotypes.

Murine model study of the practical implication of trypanosome-induced immunosuppression in vaccine-based disease control programmes

The relevance of trypanosome-induced immunosuppression in relation to the efficacy of vaccine-induced immunity was studied in mice. Mice were immunised with crude Trichinella spiralis muscle larvae homogenate vaccine and infected with T. spiralis and/or Trypanosoma brucei. Vaccination significantly decreased adult worm burden ( p<0.05) and accelerated worm expulsion in mice infected with T. spiralis only. T. brucei superinfection resulted in monocytosis, suppressed eosinophilia, significant decrease in PCV ( p<0.001), higher numbers of adult worms ( p<0.001) and failure to expel all adult worms by Day 12 post infection (p.i.). Regardless, they produced anti- Trichinella IgG 1 responses similar to those of the vaccinated non- T. brucei-infected group. T. brucei also suppressed the proliferative responses of spleen cells to stimulation with Con A and T. spiralis antigen, and induced strong production of interferon-gamma (IFN-γ) in culture supernatants of antigen stimulated spleen and mesenteric lymph node cells. Interleukin-5 (IL-5) production was suppressed by T. brucei in supernatants of Con A- and antigen-stimulated spleen cells. It was concluded that trypanosome infections and the associated immunosuppression are of great practical significance in trypanosome endemic areas, especially with regards to disease control programmes involving vaccine-induced herd immunity.

IL-13-mediated worm expulsion is B7 independent and IFN-gamma sensitive.

B7 costimulation is a required component of many type 2 immune responses, including allergy and protective immunity to many nematode parasites. This response includes elevations in Th2 cytokines and associated effector functions including elevations in serum IgG1 and IgE and parasite expulsion. In studies of mice infected with Trichuris muris, blocking B7 ligand interactions inhibited protective immunity, suppressed IL-4 production, and enhanced IFN-gamma production, but unexpectedly did not inhibit production of the Th2 cytokine, IL-13. Blocking both IFN-gamma and B7 restored protective immunity, which was IL-13 dependent, but did not restore IL-4 or associated IgE responses. Although IL-13 was required for worm expulsion in mice in which both IFN-gamma and B7 were blocked, IL-4 could mediate expulsion in the absence of both IL-13 and IFN-gamma. These studies demonstrate that 1) B7 costimulation is required to induce IL-4, but not IL-13 responses; 2) IL-13 is elevated in association with the IFN-gamma response that occurs following inhibition of B7 interactions, but can only mediate IL-4-independent protection when IFN-gamma is also inhibited; and 3) increased IL-13 production, in the absence of increased IL-4 production, is not associated with an IgE response, even in the absence of IFN-gamma.

Intestinal mucosal mast cells in Nippostrongylus-infected mice: Lack of sensitivity to corticosteroids

Immune reactions to enteric nematodes, in which mast cells are thought to play an important role, are abrogated following corticosteroid treatment of host animals. This is probably due, at least in part, to inhibition of cytokine production by T cells. It has proved difficult to block worm expulsion in mice with corticosteroids. We have therefore examined the effects of corticosteroids on mast cell numbers and concentrations of the mast cell granule-specific serine protease Mouse Intestinal Mast Cell Protease (MIMCP) in the intestines of mice infected with Nippostrongylus brasiliensis. Mucosal mast cell (MMC) numbers and concentrations of MIMCP were unaltered by steroid treatment. This is in marked contrast to Nippostrongylus-infected rats which showed decreases in both mast cell numbers and concentrations of the rat mucosal mast cell protease RMCP II after steroid treatment. This suggests that differentiated murine MMC are less dependent on T cells than those of the rat.

Transfer of immunity to Trichinella spiralis in the mouse with mesenteric lymph node cells: time of appearance of effective cells in donors and expression of immunity in recipients.

Cells capable of transferring immunity to Trichinella spiralis, i.e. of accelerating adult worm expulsion, were present in the mesenteric lymph nodes of mice infected for 4, 6 or 8 days, but not in mice infected for only 2 days. The time-course of worm expulsion in mice infected on the day of transfer was similar in recipients of day 4 or day 8 cells, expulsion becoming marked only when the recipients had been infected for at least 6 days. Transfer of cells 4 or 6 days after infection did not result in an accelerated worm expulsion; transfer 1 or 2 weeks before infection did not enhance the level of immunity in recipient mice. In contrast to the results obtained with mesenteric lymph node cells (MLNC) on immunity was transferred when recipients were given spleen cells taken from donors infected for 8 days. It is suggested that MLNC do not cause worm expulsion directly, but cooperate with another component of the host's defence mechanism. Accelerated expulsion in recipients of cells was accompanied by a premature decline in fecundity of female worms. Evidence is presented to show that worm expulsion and impaired reproduction may represent independent aspects of the immune response to T. spiralis.

Immune expulsion of Trichuris muris from mice during a primary infection: analysis of the components involved.

Immune serum accelerated the expulsion of Trichuris muris when transferred into normal mice on days 0 and 3 after infection, but had no effect when the recipient mice had been immunosuppressed by sublethal irradiation or by cortisone treatment. Delaying serum transfer until days 7 and 8 in normal mice failed to accelerate expulsion, although immune mesenteric lymph node cells (MLNC) accelerated expulsion whether transferred early or late in infection. Expulsion from NIH mice, normally complete by 12 days, was prevented by sublethal irradiation given as late as 9 days after infection, but could be restored by subsequent transfer of immune MLNC or, to a lesser degree, non-immune MLNC. Immune MLNC were unable to restore worm expulsion in mice irradiated before infection. These results are interpreted as showing that the immune expulsion of T. murius from mice during a primary infection requires the sequential activities of antibody-mediated and lymphoid cell-mediated components.