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The immunological consequences of nematode infection.

Nematode infections in the gut induce a strong immune response which is rapidly detected parenterally. The response is thymus-dependent and long-lasting and involves both antibodies and cell-mediated reactions. The immunological response to unrelated antigens, tumours and other infectious organisms is altered in animals infected with nematodes. Both antibodies and sensitized lymphocytes participate in the immune response which affects the nematodes themselves, and characteristically the lymphocyte-dependent step cannot act in lactating animals and is neither induced nor able to act in young animals. Present evidence suggests that, despite their well-known association with helminth infections, parasite rejection from the gut does not require the participation of IgE antibodies, mast cells or eosinophils. Homing of lymphoblasts from the mesenteric lymph node or thoracic duct lymph to the small intestine is increased in rats and mice infected with Nippostrongylus brasiliensis or Trichinella spiralis and the increase is antigenically non-specific. In mice infected with T. spiralis this increase is represented mainly by thymus-derived lymphoblasts.

Animals↗

Host immune responses are necessary for density dependence in nematode infections.

Nematode infections are subject to density-dependent effects on their establishment, survivorship and fecundity within a host. These effects act to regulate and stabilize the size of nematode populations. Understanding how these density-dependent effects occur is important to guide the development of control strategies against parasitic nematodes and the diseases that they cause. These density-dependent effects have been hypothesized to result from intraspecific competition between parasites for limited resources or from the action of host immune responses. However, no specific evidence exists to distinguish between these two hypotheses. We find that in nematode (Strongyloides ratti) infections, density-dependent effects on parasite establishment, survivorship and fecundity are mediated by the host immune response. These density-dependent effects are only observed late in primary infections and no density-dependent effects are observed in infections in immuno-compromised animals. We find no evidence for intraspecific competition between parasites in experimental infections over a range of doses that encompasses all that is observed in natural infections. We conclude that density-dependent effects due to the immune response will act to regulate S. ratti infections before competition for space or nutrients within the host gut ever occurs.

Animals↗

Immune-mediated regulation of chronic intestinal nematode infection.

Gastrointestinal nematode infection is extremely prevalent worldwide in humans and animals. Infection levels vary between individuals in infected populations and exhibit a negative binomial distribution, and some individuals appear to be predisposed to certain infection levels. Moreover, infection tends to be chronic, despite evidence for the acquisition of some degree of acquired immunity. The host is subject to constant and repeated antigenic challenge, and individuals vary in the response they make. While a considerable amount of information is emerging on the immunoregulatory mechanisms operating during acute nematode infection from a variety of laboratory model systems, relatively little work has been carried out on the immune mechanisms underlying chronic infection. This review details some of the work that has addressed this important facet of gut nematode infection, highlighting studies from model systems that give insight into the induction of nonprotective immunity, while at the same time avoiding the induction of host-damaging pathology.

Animals↗

Formulation of entomopathogenic nematode-infected cadavers.

Entomopathogenic nematodes are commercially applied in aqueous suspension. These biocontrol agents may also be applied in nematode-infected insect cadavers, but this approach may entail problems in storage and ease of handling. We determined the feasibility of formulating nematode-infected insect cadavers to overcome these hindrances. All experiments were conducted with Heterorhabditis bacteriophora Poinar and Galleria mellonella (L.). Nonformulated cadavers were used as controls. Of 19 formulations tested (including combinations of starches, flours, clays, etc.) 1 (starch-clay combination) was found to adhere to the cadaver and to have no significant deleterious effects on nematode reproduction and infectivity; other formulations exhibited poor adhesion or reduced nematode reproduction. Two formulations enabled cadavers to be partially desiccated without affecting reproduction; other formulations and nonformulated cadavers exhibited reduced reproduction upon desiccation. Four-day-old cadavers were more amenable to desiccation than 8-day-old cadavers. Formulated cadavers were more resistant to rupturing and sticking together during agitation than nonformulated cadavers.

Animals↗

Increased intestinal muscle contractility and worm expulsion in nematode-infected mice.

Intestinal nematode infections are accompanied by mucosal inflammation and an increase in propulsive motor activity that may contribute to parasite eviction from the gut. To examine whether differences in worm expulsion correspond to the increased intestinal muscle contractility that accompanies nematode infection, we studied mice with genetically determined differences in their ability to expel the nematode parasite Trichinella spiralis. Specifically, we examined isometric contraction of longitudinal muscle, worm counts, and inflammation, as measured by myeloperoxidase activity, in two strains of mice infected with T. spiralis. The strong responder strain, NIH Swiss, expelled the parasites by day 16 postinfection, whereas the poorer responding B10.BR strain was still heavily infected by day 21 postinfection. However, both strains developed similar increases in jejunal myeloperoxidase activity. Both strains demonstrated increased isometric tension development after infection, but peak tension occurred earlier in NIH Swiss mice (day 8 vs. day 12 postinfection) and was of significantly greater magnitude than in B10.BR mice. We conclude that the ability to expel T. spiralis from the small bowel is not related to the degree of granulocyte-dependent mucosal inflammation but is reflected in the magnitude of the accompanying increase in force generation by intestinal smooth muscle.

Animals↗

Nematode infections are risk factors for staphylococcal infection in children.

Nematode infection may be a risk factor for pyogenic liver abscess in children and we hypothesized that the immunomodulation induced by those parasites would be a risk factor for any staphylococcal infection in children. The present study was designed to compare, within the same hospital, the frequency of intestinal nematodes and Toxocara infection in children with and without staphylococcal infections. From October 1997 to February 1998, 80 children with staphylococcal infection and 110 children with other diseases were submitted to fecal examination, serology for Toxocara sp., evaluation of plasma immunoglobulin levels, and eosinophil counts. Mean age, gender distribution, birthplace, and socioeconomic conditions did not differ significantly between the two groups. Frequency of intestinal nematodes and positive serology for Toxocara, were remarkably higher in children with staphylococcal infections than in the non-staphylococcal group. There was a significant correlation between intestinal nematodes or Toxocara infection and staphylococcal infection in children, reinforced by higher eosinophil counts and higher IgE levels in these children than in the control group. One possible explanation for this association would be the enhancement of bacterial infection by the immunomodulation induced by helminth infections, due to strong activation of the Th2 subset of lymphocytes by antigens from larvae and adult worms.

Animals↗

The epidemiology of nematode infections of sheep.

Nematode parasites have been a major factor limiting sheep production in New Zealand for more than 100 years. Twenty-nine species of nematodes were unintentionally introduced with sheep into New Zealand, but it is principally species of Haemonchus, Ostertagia, Trichostrongylus, Nematodirus and Cooperia that are associated with production losses and clinical disease. The seasonal dynamics of nematode infection are the consequence of complex inter-relationships between the sheep, their husbandry and the prevailing climate. The patterns of pasture contamination by nematode eggs and then larvae and the subsequent levels of infection in ewes and lambs are broadly similar throughout New Zealand. Numbers of infective larvae on pasture build up over summer to a peak in autumn/early winter with, in some years, a spring peak derived from the parturient rise in faecal nematode egg counts (FEC), expressed in eggs per gram of faeces (epg), in lactating ewes. The immune capability of lambs is initially low but increases with the magnitude and duration of exposure to infection. Once significant immunity has developed (usually by 10-12 months of age), sheep are capable of markedly restricting parasite infection, except during times of disease, malnutrition or stress. For the effective control of nematode parasites, farmers have come to rely almost exclusively on broad-spectrum anthelmintics. However, issues relating to resistance, residues and eco-toxicity increasingly threaten the sustainability of chemotherapy. In order to maintain present levels of parasite control and productivity in the long term, farmers need to integrate management practices aimed at minimising animal exposure to parasites with reduced reliance on anthelmintics.

Journal Article↗

Induction Patterns of an Extensin Gene in Tobacco upon Nematode Infection.

When sedentary endoparasitic nematodes infect plants, they induce complex feeding sites within the root tissues of their host. To characterize cell wall changes induced within these structures at a molecular level, we studied the expression of an extensin gene (coding for a major structural cell wall protein) in nematode-infected tobacco roots. Extensin gene expression was observed to be induced very early upon infection. This induction was weak, transient, and probably due to wounding during penetration and migration of the tobacco cyst nematode Globodera tabacum ssp solanacea-rum. In contrast, high extensin gene expression was observed during the whole second larval stage (an ~2-week-long phase of establishment of the feeding site) of the root knot nematode Meloidogyne javanica. During later stages of this interaction, expression gradually decreased. Extensin gene expression was found in at least three different tissues of the gall. We propose that distinct mechanisms lead to induced expression in these different cell types. The significance of these results for the understanding of plant-nematode interactions as well as the function of structural cell wall proteins, such as extensin, is discussed.

Journal Article↗

Anthelmintic activity of methyridine against experimental nematode infections in mice.

Critical studies using mice infected experimentally with nematodes (Nematospiroides dubius, Nippostrongylus muris and Heterakis spumosa) have shown methyridine to be an extremely effective anthelmintic when administered orally or subcutaneously. Comparisons of the two treatment regimes show subcutaneous administration to be the more efficient in terms of absolute dose, but neither treatment has a significant advantage in therapeutic safety margin. Methyridine has a more uniform anthelmintic action than either phenothiazine or bephenium against adult forms of the three test nematodes. In addition the drug possesses activity against all stages of certain immature nematode infections.

Animals↗

Epidemiology of human intestinal nematode infections in Wujiang and Pizhou counties, Jiangsu Province, China.

Intestinal nematode infections are considered highly endemic in the Chinese province of Jiangsu. In May 1997, the prevalence of intestinal nematodes infections was determined among all of the inhabitants aged 5 to 65 of the southern Jiangsu village of Yaojiakon (Wujiang County) and the northern Jiangsu village of Jianmiao (Pizhou County). It was determined that the prevalence of ascariasis, trichuriasis and hook worm infection was greatly reduced compared to when it was last measured in 1990. The reduction was noted to be particularly impressive in Yaojiakon village where the prevalence of ascariasis and trichiuriasis fell to 2% and 1.5% respectively. Much of this reduction was attributed to improvements in economic development which have occurred in southern Jiangsu Province at a rapid pace. In contrast, the reduction in nematode infections among villagers living in northern Jiangsu was more modest. The most striking reduction in both villages was in school-aged children who since 1988 have received yearly treatments with anthelminthic drugs. The intensity of nematode infections was investigated for hookworm where 70% of hookworm-infected Yaojiakon villagers were found to harbor light infections (< 400 eggs per gram) compared to 83% of hookworm-infected Jianmiao villagers. Necator americanus was the predominant hookworm in Yaojiakon village (South), whereas Ancylostoma duodenale predominated in Jianmiao village (North). The majority (76%) of hookworm-infected patients developed IgG antibodies against N. americanus antigen, although 20% of uninfected patients living in the village also had circulating antibodies. Intestinal nematode infections continue to be a significant public health problem in Jiangsu Province although their prevalence has decreased since 1990.

Adolescent↗

Immune-mediated alteration in gut physiology and its role in host defence in nematode infection.

Activation of the mucosal immune system of the gastrointestinal tract in nematode infection results in altered intestinal physiology, which includes changes in intestinal motility and mucus production. These changes are considered to be under direct immunological control rather than a non-specific consequence of the inflammatory reaction to the infective agent. However, little is known about the immunological basis for the changes in intestinal physiology accompanying nematode infection, or the precise role of these changes in host defence, which remains an important area to explore. In this review we describe the mechanisms by which the immune response to nematode infection influences the changes in two major cells of intestinal physiology, namely smooth muscle and goblet cells, and how these changes in intestinal physiology contribute to the host defence. Data clearly demonstrate that the T helper (Th) 2 type immune response generated by nematode infection plays an important role in the development of infection-induced intestinal muscle hypercontractility and goblet cell hyperplasia and that these immune-mediated changes in intestinal physiology are associated with worm expulsion. These observations strongly suggest that intestinal muscle contractility, goblet cell hyperplasia and worm expulsion share a common immunological basis and may be causally related. These data not only provide insights into host defence in nematode infection in the context of muscle function and goblet cell response, but also have broad implications in elucidating the pathophysiology of a wide range of gastrointestinal disorders associated with altered gut physiology.

Animals↗

Epidemiology of nematodosis in Romney lambs selectively bred for resistance or susceptibility to nematode infection.

Field trials were undertaken to compare nematode population dynamics, lamb productivity and levels of breech soiling in experimental flocks of Romney lambs selectively bred for increased resistance or susceptibility to nematode infection. In each year of the 2 year study, spring-born ewe lambs derived from Wallaceville Animal Research Centre's divergent nematode-resistant and nematode-susceptible breeding lines were grazed as separate flocks on matched farmlets from weaning (at 3 months old) until they were approximately 10-11 months old. Allocation of farmlets was reversed between Years 1 and 2 of the study to account for any possible paddock-related effects. Within each year both flocks were subjected to identical management conditions, including anthelmintic treatment (which was administered only when the overall mean faecal worm egg count measured across both genotypes reached 1500 eggs g-1). In both years, by mid-autumn (April) nematode larval infestation levels on pasture were approximately 5-6-fold greater on the farmlet grazed by susceptible (S) genotype lambs than on that grazed by their resistant (R) counterparts (Year 1: 2506 cf. 544 larvae kg-1 herbage; Year 2: 431 cf. 74 larvae kg-1 herbage). This led to 51-fold and 56-fold differences in faecal egg count between R and S lambs by late autumn (May) and winter (July) in Years 1 and 2, respectively. Although mean growth rates were similar in the R and S lambs over summer (while pasture infestation levels on the farmlets were still in the process of diverging), significantly higher growth rates occurred in the R than in the S lambs over autumn-winter in both years of the study (P < 0.01). In contrast, no significant differences in growth rate occurred in either year between male lambs derived from the nematode-resistant and nematode-susceptible breeding lines which were grazed together on another area of the Wallaceville farm from weaning until late autumn. Despite the substantially lower pasture infestation levels encountered by the R ewe lambs, they nevertheless temporarily suffered more breech soiling (dags) than their S counterparts (P < 0.01) in both years. Yearling fleece-weights of the R and S genotypes did not differ significantly in either year. Although the results of our study confirmed that there are potentially significant epidemiological benefits to be derived from breeding sheep for resistance to nematode infection, these benefits did not appear to be associated with large advantages in animal performance. Further work is needed to establish how these results should be interpreted with respect to anthelmintic drench requirements of genetically resistant animals.

Animals↗

Nematode infections of the eye: toxocariasis and diffuse unilateral subacute neuroretinitis.

In many parts of the world, parasitic infections of the eye are a major cause of blindness. The parasites Toxocara canis, Onchocerca volvulus, Taenia solium, Ancylostoma caninum, and Cysticercus celulosae all have been responsible for blinding ocular infections. The nematodes T. canis and Toxocara cati are parasitic roundworms that infect dogs (toxocarosis), other canidae, and cats. Ocular toxocariasis is an uncommon worldwide infection caused by the nematode larvae of T. canis, commonly found in dogs. Human transmission is usually via geophagia, the ingestion of food contaminated with Toxocara eggs, or contact with infected puppies, often resulting in devastating ocular or systemic effects. Ocular toxocariasis is typically a monocular disease of young children, and its clinical findings include posterior and peripheral retinochoroiditis, optic papillitis, and endophthalmitis. The inflammatory response created by ocular involvement may result in epiretinal membrane formation, traction retinal detachment, and combined traction-rhegmatogenous retinal detachment. Diffuse unilateral subacute neuroretinitis is another ocular parasitic infection that usually results in severe visual loss. Evidence suggests that diffuse unilateral subacute neuroretinitis is caused by a solitary unidentified nematode of two different sizes, but to date, only a small number of nematodes have been recovered from eyes affected with the infection. Diffuse unilateral subacute neuroretinitis occasionally can affect the fellow eye.

Antiprotozoal Agents↗

Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections.

Immune responses associated with intestinal nematode infections are characterized by the activation of T-helper 2 (Th2) cells. Previous studies demonstrated that during Trichinella spiralis infection, Th2 cells contribute to the development of intestinal muscle hypercontractility and to worm eviction from the gut, in part through signal transducer and activator of transcription factor 6 (Stat6). Interleukin-9 (IL-9), a Th2-cell-derived cytokine, has pleiotropic activities on various cells that are not mediated through Stat6. In this study, we investigated the role of IL-9 in the generation of enteric muscle hypercontractility in mice infected with the intestinal parasite T. spiralis and the cecal parasite Trichuris muris. Treatment of mice with IL-9 enhanced infection-induced jejunal muscle hypercontractility and accelerated worm expulsion in T. spiralis infection. These effects were associated with an up-regulation of IL-4 and IL-13 production from in vitro-stimulated spleen cells. In addition, increases in the level of intestinal goblet cells and in the level of mouse mucosal mast cell protease 1 (MMCP-1) in serum were observed in infected mice following IL-9 administration. However, the neutralization of IL-9 by anti-IL-9 vaccination or by anti-IL-9 antibody had no significant effect on worm expulsion or muscle contraction in T. spiralis-infected mice. In contrast, the neutralization of IL-9 significantly attenuated T. muris infection-induced colonic muscle hypercontractility and inhibited worm expulsion. The attenuated expulsion of the parasite by IL-9 neutralization was not accompanied by changes in goblet cell hyperplasia or the MMCP-1 level. These findings suggest that IL-9 contributes to intestinal muscle function and to host protective immunity and that its importance and contribution may differ depending on the type of nematode infection.

Animals↗

How do host immune responses affect nematode infections?

Host immune responses limit, and in some instances eliminate, nematode infections. There is considerable interest in enhancing these natural processes by the use of antinematode vaccines to achieve control of infection or disease. How nematodes are damaged is unclear. Worms might be damaged directly by effector cells and molecules of the immune system. Alternatively, they might be damaged by the physiological stress of their efforts to resist attack. Separating these possibilities could have important implications for approaches to the control of nematode infections and the disease that they cause.

Animals↗

Intestinal nematode infection ameliorates experimental colitis in mice.

Epidemiological studies suggest that inflammatory bowel disease (IBD) is common in developed countries and rare in countries where intestinal nematode infections are common. T cells are critical in many immune responses, including those associated with IBD and nematode infection. Among the distinct T helper (Th) cell subsets, Th1-type immune response is predominantly associated with Crohn's disease, while many nematode infections generate a strong Th2 response. The reciprocal cross regulation between Th1 and Th2 cells suggests that generation of a Th2 response by nematodes could prevent or reduce the effects of Th1-mediated diseases. In the present study, we investigated the effect of polarizing the immune response toward the Th2 type, using intestinal nematode infection, on subsequent experimental colitis. Mice were infected with the intestinal nematode Trichinella spiralis and allowed to recover before colitis was induced with dinitrobenzene sulfonic acid. The mice were sacrificed postcolitis to assess colonic damage macroscopically, histologically, and by myeloperoxidase (MPO) activity and Th cytokines. Prior nematode infection reduced the severity of colitis both macroscopically and histologically together with a decreased mortality and was correlated with a down-regulation of MPO activity, Th1-type cytokine expression in colonic tissue, and emergence of a Th2-type immune response. These results indicate a protective role of nematode infection in Th1 cell-driven inflammation and prompt consideration of a novel therapeutic strategy in IBD based on immunological distraction.

Animals↗

Immunological control of gastrointestinal nematode infections.

Control of nematode parasitism by an active manipulation of the host immune response has been a goal of veterinary and medical parasitologists for decades. The reality of achieving this goal has been questioned vigorously and demonstrations of the feasibility of using immunological control under field conditions are minimal. Nevertheless, with the rapid growth of modern biotechnology and the identification of novel parasite molecules as vaccine targets, the potential for success in this area has recently generated considerable excitement. The induction and regulation of the ruminant immune response against nematode parasites can be controlled either by management programs which include anthelmintic treatment or by vaccination. Both approaches will be discussed in this session.

Animals↗