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      Early Exposure of Infants to GI Nematodes Induces Th2 Dominant Immune Responses Which Are Unaffected by Periodic Anthelminthic Treatment

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          We have previously shown a reduction in anaemia and wasting malnutrition in infants <3 years old in Pemba Island, Zanzibar, following repeated anthelminthic treatment for the endemic gastrointestinal (GI) nematodes Ascaris lumbricoides, hookworm and Trichuris trichiura. In view of the low intensity of worm infections in this age group, this was unexpected, and it was proposed that immune responses to the worms rather than their direct effects may play a significant role in morbidity in infants and that anthelminthic treatment may alleviate such effects. Therefore, the primary aims of this study were to characterise the immune response to initial/early GI nematode infections in infants and the effects of anthelminthic treatment on such immune responses. The frequency and levels of Th1/Th2 cytokines (IL-5, IL-13, IFN-γ and IL-10) induced by the worms were evaluated in 666 infants aged 6–24 months using the Whole Blood Assay. Ascaris and hookworm antigens induced predominantly Th2 cytokine responses, and levels of IL-5 and IL-13 were significantly correlated. The frequencies and levels of responses were higher for both Ascaris positive and hookworm positive infants compared with worm negative individuals, but very few infants made Trichuris-specific cytokine responses. Infants treated every 3 months with mebendazole showed a significantly lower prevalence of infection compared with placebo-treated controls at one year following baseline. At follow-up, cytokine responses to Ascaris and hookworm antigens, which remained Th2 biased, were increased compared with baseline but were not significantly affected by treatment. However, blood eosinophil levels, which were elevated in worm-infected children, were significantly lower in treated children. Thus the effect of deworming in this age group on anaemia and wasting malnutrition, which were replicated in this study, could not be explained by modification of cytokine responses but may be related to eosinophil function.

          Author Summary

          Infants and very young children commonly become infected with intestinal nematode infections. However, the worm burdens are generally very light, so a beneficial effect of deworming on wasting malnutrition and anaemia in this age group which we have demonstrated was unexpected and the mechanism unclear. To investigate this, we have, for the first time, determined whether such worm infections in infants induce significant immune reactions which might be detrimental to nutrition and growth e.g. by inducing inflammation in the gut or by cytokine effects on erythropoiesis. We also determined if such responses are modulated by regular deworming over a 9 month period. Peripheral blood cells from infants infected with Ascaris and hookworms in particular responded to stimulation with worm antigens, producing predominantly Th2 cytokines. Although the Th2 cytokine responses in the periphery were not significantly altered by deworming, the levels of eosinophils, which are regulated by the Th2 cytokine, IL-5, were lower after treatment. It is possible that eosinophils play a role in gut pathology leading to wasting malnutrition and anaemia in the very young and that this effect is reduced by deworming.

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          Most cited references 70

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          Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm.

          The three main soil-transmitted helminth infections, ascariasis, trichuriasis, and hookworm, are common clinical disorders in man. The gastrointestinal tract of a child living in poverty in a less developed country is likely to be parasitised with at least one, and in many cases all three soil-transmitted helminths, with resultant impairments in physical, intellectual, and cognitive development. The benzimidazole anthelmintics, mebendazole and albendazole, are commonly used to remove these infections. The use of these drugs is not limited to treatment of symptomatic soil-transmitted helminth infections, but also for large-scale prevention of morbidity in children living in endemic areas. As a result of data showing improvements in child health and education after deworming, and the burden of disease attributed to soil-transmitted helminths, the worldwide community is awakening to the importance of these infections. Concerns about the sustainability of periodic deworming with benzimidazole anthelmintics and the emergence of resistance have prompted efforts to develop and test new control tools.
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            RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract.

            Gastrointestinal (GI) nematode infections are an important public health and economic concern. Experimental studies have shown that resistance to infection requires CD4(+) T helper type 2 (Th2) cytokine responses characterized by the production of IL-4 and IL-13. However, despite >30 years of research, it is unclear how the immune system mediates the expulsion of worms from the GI tract. Here, we demonstrate that a recently described intestinal goblet cell-specific protein, RELMbeta/FIZZ2, is induced after exposure to three phylogenetically distinct GI nematode pathogens. Maximal expression of RELMbeta was coincident with the production of Th2 cytokines and host protective immunity, whereas production of the Th1 cytokine, IFN-gamma, inhibited RELMbeta expression and led to chronic infection. Furthermore, whereas induction of RELMbeta was equivalent in nematode-infected wild-type and IL-4-deficient mice, IL-4 receptor-deficient mice showed minimal RELMbeta induction and developed persistent infections, demonstrating a direct role for IL-13 in optimal expression of RELMbeta. Finally, we show that RELMbeta binds to components of the nematode chemosensory apparatus and inhibits chemotaxic function of a parasitic nematode in vitro. Together, these results suggest that intestinal goblet cell-derived RELMbeta may be a novel Th2 cytokine-induced immune-effector molecule in resistance to GI nematode infection.
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              Malnutrition and parasitic helminth infections.

              The Global Burden of Disease caused by the 3 major intestinal nematodes is an estimated 22.1 million disability-adjusted life-years (DALYs) lost for hookworm, 10.5 million for Ascaris lumbricoides, 6.4 million for Trichuris trichiura, and 39.0 million for the three infections combined (as compared with malaria at 35.7 million) (World Bank, 1993; Chan et al. 1994); these figures illustrate why some scarce health care resources must be used for their control. Strongyloides stercoralis is the fourth most important intestinal worm infection; its nutritional implications are discussed, and the fact that its geographic distribution needs further study is emphasized. Mechanisms underlying the malnutrition induced by intestinal helminths are described. Anorexia, which can decrease intake of all nutrients in tropical populations on marginal diets, is likely to be the most important in terms of magnitude and the probable major mechanism by which intestinal nematodes inhibit growth and development. We present a revised and expanded conceptual framework for how parasites cause/aggravate malnutrition and retard development in endemic areas. Specific negative effects that a wide variety of parasites may have on gastrointestinal physiology are presented. The synergism between Trichuris and Campylobacter, intestinal inflammation and growth failure, and new studies showing that hookworm inhibits growth and promotes anaemia in preschool (as well as school-age) children are presented. We conclude by presenting rationales and evidence to justify ensuring the widest possible coverage for preschool-age children and girls and women of childbearing age in intestinal parasite control programmes, in order to prevent morbidity and mortality in general and specifically to help decrease the vicious intergenerational cycle of growth failure (of low-birth-weight/intrauterine growth retardation and stunting) that entraps infants, children and girls and women of reproductive age in developing areas.

                Author and article information

                Role: Editor
                PLoS Negl Trop Dis
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                May 2009
                19 May 2009
                : 3
                : 5
                [1 ]Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [2 ]Public Health Laboratory Ivo de Carneri, Wawi, Chake Chake, Pemba Island, Zanzibar, United Republic of Tanzania
                [3 ]Centre for Human Nutrition, Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [4 ]School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
                [5 ]RTI International, Dar es Salam, United Republic of Tanzania
                [6 ]Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America
                Sabin Vaccine Institute, United States of America
                Author notes

                Conceived and designed the experiments: VJW REW JMT RJS QDB. Performed the experiments: VJW SMA HSH QDB. Analyzed the data: VJW QDB. Wrote the paper: VJW QDB. Responsible for parasitology: DG. Supplied hookworm antigen and reviewed paper: DIP. Supervised fieldwork: MRM HJH.

                Wright et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 12
                Research Article
                Immunology/Immunity to Infections
                Infectious Diseases/Epidemiology and Control of Infectious Diseases
                Infectious Diseases/Helminth Infections

                Infectious disease & Microbiology


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