Social contact behaviors are associated with infection status for Trichuris sp. in wild vervet monkeys (Chlorocebus pygerythrus).

Social grooming in the animal kingdom is common and serves several functions, from removing ectoparasites to maintaining social bonds between conspecifics. We examined whether time spent grooming with others in a highly social mammal species was associated with infection status for gastrointestinal parasites. Of six parasites detected, one (Trichuris sp.) was associated with social grooming behaviors, but more specifically with direct physical contact with others. Individuals infected with Trichuris sp. spent significantly less time grooming conspecifics than those not infected, and time in direct contact with others was the major predictor of infection status. One model correctly predicted infection status for Trichuris sp. with a reliability of 95.17% overall when the variables used were time spent in direct contact and time spent grooming others. This decrease in time spent grooming and interacting with others is likely a sickness behavior displayed by individuals with less energy or motivation for non-essential behaviors. This study emphasizes the possible links between host behavior and parasitic infections and highlights the need for an understanding of a study population's parasitic infections when attempting to interpret animal behavior.

Whipworm and roundworm infections.

Trichuriasis and ascariasis are neglected tropical diseases caused by the gastrointestinal dwelling nematodes Trichuris trichiura (a whipworm) and Ascaris lumbricoides (a roundworm), respectively. Both parasites are staggeringly prevalent, particularly in tropical and subtropical areas, and are associated with substantial morbidity. Infection is initiated by ingestion of infective eggs, which hatch in the intestine. Thereafter, T. trichiura larvae moult within intestinal epithelial cells, with adult worms embedded in a partially intracellular niche in the large intestine, whereas A. lumbricoides larvae penetrate the gut mucosa and migrate through the liver and lungs before returning to the lumen of the small intestine, where adult worms dwell. Both species elicit type 2 anti-parasite immunity. Diagnosis is typically based on clinical presentation (gastrointestinal symptoms and inflammation) and the detection of eggs or parasite DNA in the faeces. Prevention and treatment strategies rely on periodic mass drug administration (generally with albendazole or mebendazole) to at-risk populations and improvements in water, sanitation and hygiene. The effectiveness of drug treatment is very high for A. lumbricoides infections, whereas cure rates for T. trichiura infections are low. Novel anthelminthic drugs are needed, together with vaccine development and tools for diagnosis and assessment of parasite control in the field.

Accumulation of eosinophils in intestine-draining mesenteric lymph nodes occurs after Trichuris muris infection.

Eosinophils have recently been demonstrated capable of localizing to lymph nodes that drain mucosal surfaces, in particular during T helper 2 (Th2) responses. Resistance of mice to infection with the gastrointestinal nematode Trichuris muris depends critically on mounting of a Th2 response and represents a useful model system to investigate Th2 responses. Following infection of resistant BALB/c mice with T. muris, we observed accumulation of eosinophils in intestine-draining mesenteric lymph nodes (MLNs). The accumulation of MLN eosinophils was initiated during the second week of infection and peaked during worm expulsion. In contrast, we detected a comparably late and modest increase in eosinophil numbers in the MLNs of infected susceptible AKR mice. MLN eosinophils localized preferentially to the medullary region of the lymph node, displayed an activated phenotype and contributed to the interleukin-4 (IL-4) response in the MLN. Despite this, mice genetically deficient in eosinophils efficiently generated IL-4-expressing CD4(+) T cells, produced Th2 cytokines and mediated worm expulsion during primary T. muris infection. Thus, IL-4-expressing eosinophils accumulate in MLNs of T. muris-infected BALB/c mice but are dispensable for worm expulsion and generation of Th2 responses, suggesting a distinct or subtle role of MLN eosinophils in the immune response to T. muris infection.

Mechanisms underlying gut dysfunction in a murine model of chronic parasitic infection.

Irritable bowel syndrome (IBS) is common in countries where chronic parasitic infestations are endemic. However, the relationship between parasitic infection and IBS is not clear. The aim of this study was to examine whether chronic parasitic infection is accompanied by gut dysfunction and whether the continued presence of the parasite is required for the maintenance of the dysfunction. We used chronic Trichuris muris infection in Th1-biased susceptible AKR mice to evaluate this relationship. AKR mice were infected with T. muris and were euthanized on various days postinfection (pi) to examine worm burden, muscle function, and immune and inflammatory responses. Mice were treated with the anthelmintic oxantel pamoate to assess the effect of eradication of infection on muscle function. Infection resulted in persistence of the parasite, elevated IFN-γ, and increased MPO activity evident at 45 days pi. This was accompanied by a reduction in muscle contractility and excitatory innervation. Whereas parasite eradication at 7 days pi normalized IFN-γ and muscle contractility, eradication at 28 days pi failed to normalize muscle contractility. Administration of dexamethasone after parasite eradication normalized all parameters. Anthelmintic treatment improved histology except for eosinophils, which were normalized by subsequent dexamethasone therapy. Persistent gut dysfunction is independent of the continued presence of the parasite and is maintained by inflammatory process that includes eosinophils. Thus data in this preclinical model suggest that parasitic infection could be a cause of IBS, and the lack of symptomatic improvement following eradication is insufficient evidence to refute a causal relationship between the infection and IBS.

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

BACKGROUND & AIMS: Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. METHODS: AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. RESULTS: T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. CONCLUSIONS: Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.

Foodborne nematodal infections in hospitalized patients from a southwestern Romanian county.

OBJECTIVES: Caras-Severin County presented the highest incidence of human trichinellosis (108.5 cases per 100,000 inhabitants) throughout Romania in 1993. This study aimed at providing an overview of the epidemiological and clinical characteristics of persons from this county hospitalized with nematodal infections between 1996 and 2008. PATIENTS AND METHODS: Data were collected from the medical records of 269 patients admitted to two infectious diseases hospitals and found to have nematode helminthic infections. RESULTS: Of the study group, 250 patients (92.9%) presented with trichinellosis, 10 (3.7%) with ascariasis, 7 (2.6%) with trichuriasis, and 2 (0.8%) with ascariasis and trichuriasis coinfections. Geohelminthic infections prevailed in children (68.4%). Giardiasis, a protozoan parasitic disease, was also found in 21 patients (7.8%). CONCLUSIONS: Although trichinellosis cases decreased in this county, public health authorities must remain aware because new outbreaks may occur at any time as it happened in the neighboring counties. Regarding geohelminthiasis, parents must be aware of the potential risk of acquiring these infections and the major complications that may follow.

IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD.

Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of T(h)1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4(+) T cell IFN-gamma production through effects on Tbet, a key T(h)1 transcription factor. We also found that its ability to suppress T(h)2 responses, which was clearly evident in helminth-infected IL-10-/-IL-27R-/- mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote T(h)1-type and suppress T(h)2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.

Dendritic cells have a crucial role in the production of cytokines in mesenteric lymph nodes of B10.BR mice infected with Trichuris muris.

Dendritic cells bridge innate and adaptive immunity and establish protective immunity to pathogens. Protection against the murine nematode parasite Trichuris muris depends on the T helper 2 (Th2) response and requires the Th2 cytokines interleukin 4 (IL-4), IL-10, or IL-13. To examine if the Th2 response to T. muris infection is regulated by CD11c(+)B220(-) dendritic cells in mesenteric lymph nodes, dendritic cell-enriched and dendritic cell-depleted fractions were obtained from mesenteric lymph node cells of T. muris-infected mice, and production of cytokines in cultures of these fractions was measured. At day 14 postinfection, no worm expulsion was observed, and high levels of interferon gamma production occurred in dendritic cell-enriched fractions. Expulsion of worms occurred on days 20 and 25 postinfection, and IL-10 production was induced in dendritic cell-enriched fractions on these 2 days. No cytokine production was observed in mesenteric lymph node cells and dendritic cell-depleted fractions during T. muris infection. The occurrence of worm expulsion was consistent with IL-10 production in dendritic cell-enriched fractions. IL-10 inhibits Th1 cells and promotes the Th2 response, and results from this study suggest that CD11c(+)B220(-) dendritic cells in the mesenteric lymph nodes are required for IL-10 production and the IL-10-dependent protective Th2 response.

Determination of fecal occult blood in primary schoolchildren infected with Trichuris trichiura.

A correlation of Trichuris trichiura infection and fecal occult blood detection was conducted in 146 primary schoolchildren in Narathiwat Province, Thailand. The Kato-Katz thick smear method was used for determining egg counts and stated as eggs per gram of feces (epg). The number of T. trichiura eggs was categorized as class I (1-499 epg), class 11 (500-4,999 epg), and class III (> 5,000 epg), according to the relation between infection intensity and reduced hemoglobin concentration. Each fecal sample was processed to detect occult blood using a guaiac-based test (Hema-Screen, USA) and an immunochromatographic-based test (HEXAGON OBTI test, Germany). There were 50 schoolchildren without parasitic infection in the control group. Of 96 cases with T. trichiura infection, 85 and 11 children were classified in the class I and class II groups, respectively, but no subjects were in the class III group. Positive occult blood detection results in the control, class I, and class II groups using the guaiac and the immunochemical tests were 0, 3.5, and 9.1% (p=0.19), and 0, 2.4, and 36.4%, (p<0.0001) respectively. This study suggests that T. trichiura infection with an intensity of 500 epg or greater may be associated with intestinal bleeding.

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.

The role of CD8+ cells in the establishment and maintenance of a Trichuris muris infection.

Chronic infection by the caecal-dwelling intestinal murine nematode Trichuris muris occurs if given as a high-dose infection to 'susceptible' AKR mice or as a low-dose infection to the normally 'resistant' C57BL/6 mouse strain. Both regimes result in a type 1 cytokine response, i.e. high levels of IFN-gamma and IL-12. Here we show this susceptible response is associated with a large population of CD8(+) IFN-gamma(+) cells within the mesenteric lymph nodes and numerous CD8(+) cells infiltrating the caecal mucosa. Despite this, the in vivo abolition of CD8(+) cells within AKR and C57BL/6 mice, either prior to infection or once infection has become established, failed to affect chronicity, implying that CD8(+) T cells are not essential for the initiation or maintenance of the susceptible response to T. muris. Interestingly, the percentage of IFN-gamma(+) CD4(+) cells increased in treated groups, perhaps in a compensatory role. The majority of antigen-specific cytokine responses were comparable in both treated and control groups, although IL-5 was fivefold higher in animals receiving anti-CD8 mAbs and IFN-gamma was also raised in treated mice. Mastocytosis was unaltered by CD8 depletion, however, paradoxically, eosinophilia within the caecum was reduced in treated mice. Together these data clearly demonstrate that CD8(+) T cells are associated with chronic T. muris infection; however, these cells are dispensable for both the early and late phases of this response, but do appear to play a role in the regulation of certain cytokines and caecal eosinophilia.

Age- and infection intensity-dependent cytokine and antibody production in human trichuriasis: the importance of IgE.

The cytokine and antibody response to Trichuris trichiura infection was determined for 96 persons living in an area where the parasite is highly endemic and infection exhibits a convex age intensity profile. In response to stimulation with T. trichiura antigen, a small proportion of the study group produced interleukin (IL)-4 (7%), IL-9 (5%), and IL-13 (17%). A larger proportion produced IL-10 (97%), tumor necrosis factor (TNF)-alpha (93%), and interferon (IFN)-gamma (32%). The levels of TNF-alpha (P =.016) and IFN-gamma (P =.012) significantly increased with age, suggesting a switch to a more chronic infection phenotype. The predominant parasite-specific antibodies produced were IgG1, IgG4, IgA, and IgE. Unlike the IgG subclasses and IgA, parasite-specific IgE correlated negatively with infection intensity, as defined by egg output (P =.008), and positively with host age (P =.010). These findings suggest a mixed cytokine response in trichuriasis and an IgE-associated level of protection.

Trichuris Dysentery Syndrome: evidence that it may be underdiagnosed in Kelantan.

The prevalence rate of trichuriasis in children in certain areas of Kelantan is high. However the Trichuris Dysentery Syndrome (TDS), a condition in children characterized by chronic diarrhoea, stunting and anaemia is said to be rare. A recent change in policy at our institution to lower the threshold for undertaking colonoscopy in children with chronic diarrhoea resulted in the detection of 6 cases of TDS in less than a year. The median age was 7 years (range 3-13) and the median duration of symptoms before diagnosis was 2 years (range 1-8). The insidious nature of TDS and the low level of awareness of this condition even among health care workers may result in considerable underdiagnosis.

Anthelmintic treatment of rural Bangladeshi children: effect on host physiology, growth, and biochemical status.

BACKGROUND: The effect of helminth infestation on the nutrition, growth, and physiology of the host is still poorly understood. Anthelmintic treatment of children in developing countries has had varying success in terms of growth improvements. OBJECTIVE: The objective of this study was to assess the effect of regular deworming on child growth, physiology, and biochemical status. DESIGN: The study was a 12-mo longitudinal intervention in 123 Bangladeshi children aged 2-5 y. Treatment (mebendazole) or placebo tablets were administered every 2 mo for 8 mo and again at 12 mo. Weight, height, midupper arm circumference, intestinal permeability, plasma albumin, alpha(1)-antichymotrypsin, and total protein concentration were assessed every 2 mo. RESULTS: Treatment with mebendazole reduced the prevalence of Ascaris lumbricoides from 78% to 8%, of Trichuris trichiura from 65% to 9%, and of hookworm from 4% to 0%. There was no significant difference in the growth of treated children compared with those given placebo tablets. No changes in intestinal permeability or plasma albumin were observed after deworming. Significant decreases in total protein (P<0.001) and alpha(1)-antichymotrypsin (P<0.001) were observed in the treatment group, indicating possible reductions in inflammation and immunoglobulin concentration after deworming. A significant increase in the prevalence of Giardia intestinalis (from 4% to 49%) in the treatment group was associated with a short-term reduction in weight (P = 0.02) and higher intestinal permeability (P <0.001) in infected subjects. No long-term effects of G. intestinalis on growth were observed. CONCLUSION: Low-intensity helminth infections, predominantly of A. lumbricoides and T. trichiura, do not contribute significantly to the poor growth and biochemical status of rural Bangladeshi children.

Experimental infection of pigs with three dose levels of Trichuris suis.

The objective of the study was to follow the course of Trichuris suis infection in pigs given infective eggs at low (400 eggs), medium (4,000 eggs) and high inoculation dose (40,000 eggs), respectively. Interestingly, despite a 100-fold difference in dose level no significant difference was found in either blood parameters, total faecal egg excretion, fecundity or worm burdens at necropsy 12 weeks post inoculation. The highest and lowest median faecal egg output was found in the medium and high dose group, respectively. With increasing dose level, worm size, establishment and prevalence of T. suis positive pigs decreased while worms were dislocated aborally. In addition there was a highly significant correlation between female worm burden and faecal egg excretion.

Effect of intestinal helminthiasis on nutritional status of schoolchildren.

This study was conducted in a rural agricultural area in Siniloan, Republic of the Philippines. The subjects were the school children. The nutritional status of 58 children infected with helminthiasis (Ascaris lumbricoides and Trichuris trichiura) was compared with that of 19 uninfected controls. Prevalence of Ascaris and Trichuris was 40.3% and 71.4% respectively, and 36.4% of infected children had both Ascaris and Trichuris infections. Statistically significant evidence of an adverse effect of helminthiasis on serum albumin levels was found, but no child had inadequate levels of other nutrients. Although helminthic infections increase the level of immunoglobulin E (IgE) in children endemically exposed to these parasites, there was no significant difference in the serum IgE among Ascaris or Trichuris infected groups in this study.

Plasma insulin-like growth factor-1, type 1 procollagen, and serum tumor necrosis factor alpha in children recovering from Trichuris dysentery syndrome.

OBJECTIVES: To explore: 1) the relationship between plasma insulin-like growth factor-1 (IGF-1) and other markers of growth; and 2) the effect of serum concentrations of tumor necrosis factor alpha (TNF) on growth variables in children (2-10 years) stunted by Trichuris dysentery syndrome (TDS), recovering cases, and their matched controls. METHOD: Fourteen patients with TDS were admitted to the Tropical Metabolism Research Unit, treated with albendazole and iron, and then followed with matched controls (n = 28) for 1 year. Anthropometric and biochemical measurements were done on admission and then every 3 months for the year. Plasma IGF-1, the carboxyterminal propeptide of type 1 procollagen, serum TNF, total serum protein, serum albumin, and complete blood count were determined. RESULTS: Low admission plasma levels of IGF-1 in TDS cases were accompanied by high serum levels of TNF, and total serum protein, normal serum albumin, low hemoglobin, reduced collagen synthesis (low plasma carboxyterminal propeptide of type 1 procollagen), and growth failure. These variables improved significantly after treatment. Plasma levels of IGF-1 were significantly related to the Z-scores for height-for-age (r = 0.60, 0.73, 0.68) and weight-for-age (r = 0.69, 0.80, 0.69) of cases and controls, height-for-age (r = 0.51, 0.52, 0.54) and weight-for-age (r = 0.51, 0.52, 0.54) at each measurement throughout the year. Serum levels of TNF were not related to any of the growth variables. CONCLUSION: These findings may contribute to the understanding of growth failure in children affected by other forms of chronic inflammatory bowel disease.