THE GEOHELMINTHS: ASCARIS, TRICHURIS AND HOOKWORM

THE GEOHELMINTHS: ASCARIS, TRICHURIS AND HOOKWORM

World Class Parasites VOLUME 2 Volumes in the World Class Parasites book series are written for researchers, students and scholars who enjoy reading about excellent research on problems of global significance. Each volume focuses on a parasite, or group of parasites, that has a major impact on human health, or agricultural productivity, and against which we have no satisfactory defense. The volumes are intended to supplement more formal texts that cover taxonomy, life cycles, morphology, vector distribution, symptoms and treatment. They integrate vector, pathogen and host biology and celebrate the diversity of approach that comprises modern parasitological research. Series Editors Samuel J. Black, University of Massachusetts, Amherst, MA, U.S.A. J. Richard Seed, University of North Carolina, Chapel Hill, NC, U.S.A.

THE GEOHELMINTHS: ASCARIS, TRICHURIS AND HOOKWORM edited by Celia V. Holland Department of Zoology, University of Dublin and Malcolm W. Kennedy Division of Environmental and Evolutionary Biology Institute of Biomedical and Life Sciences University of Glasgow KLUWER ACADEMIC PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

0-306-47383-6 0-7923-7557-2 2

This book is dedicated to the memory of Anne Keymer (1957-1993) Biologist and friend

TABLE OF CONTENTS List of contributors...................... ix Preface.............................xi Acknowledgments.......................xv Section 1 - Epidemiologicalpatterns and consequences 1. 2. Distributions and predisposition Celia Holland and Jaap Boes.................... 1 Control strategies Lorenzo Savioli, Antonio Montresor and Marco Albonico...25 Section 2 - The cost and the damage done 3. 4. 5. Pathophysiology of intestinal nematodes Lani S. Stephenson....39 Intestinal nematodes and cognitive development Jane Kvalsvig...63 The economics of worm control Helen Guyatt....75 Section 3 - Immunology - mice, pigs and people 6. 7. 8. 9. Immune responses in humans - Ascaris Philip J. Cooper...89 Immunity and immune responses to Ascaris suum in pigs Gregers Jungersen...105 Immune responses in humans - Trichuris Helen Faulkner and Janette E. Bradley....125 The immunobiology of hookworm infection David I. Pritchard, Rupert J. Quinnell, Peter J. Hotez, J.M.Hawdon and Alan Brown....143

viii Section 4 - Genetics - mice, worms and people 10. 11. 12. 13. 14. Human host susceptibility to intestinal worm infections Sarah Williams-Blangero and John Blangero....167 Population genetics of intestinal nematodes Helen Roberts...........................185 Parasite strain diversity and host immune responses Derek Wakelin and Janette E. Bradley....199 The value of mutation scanning approaches for detecting genetic variation - implications for studying intestinal nematodes of humans Robin B. Gasser, Xingquan Zhu and Neil B. Chilton.....219 Opportunities and prospects for investigating developmentally regulated and sex-specific genes and their expression in intestinal nematodes of humans Susan E. Newton, Peter R. Boag and Robin B. Gasser......235 Section 5 - Interaction between geohelminth infections and other diseases 15. Schistosomiasis and reduced risk of atopic diseases: new insights and possible mechanisms Anita H. J. van den Biggelaar and Maria Yazdanbakhsh....269 16. Geohelminths, HIV/AIDS and TB Gadi Borkow and Zvi Bentwich...301 Index..............................319

LIST OF CONTRIBUTORS Marco Albonico Ivo de Carneri Foundation, Milan, Italy Zvi Bentwich R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 87100, Israel John Blangero Department of Genetics, South West Foundation for Biomedical Research, San Antonio, Texas 78245-0549, USA Peter R. Boag Victorian Institute of Animal Science, Attwood, Victoria 3049, Australia and Department of Veterinary Science, The University of Melbourne, Werribee, Victoria 3030, Australia Jaap Boes Danish Bacon and Meat Council, Axelborg, Axeltorv 3, DK- 1609 Copenhagen V, Denmark Gadi Borkow R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 87100, Israel Janette E. Bradley School of Life and Environmental Sciences, University of Nottingham, Nottingham, NG7 2RD, UK Alan Brown Boots Science Building, School of Pharmacy, University of Nottingham, NG7 2RD, UK Neil B. Chilton Department of Veterinary Science, The University of Melbourne, Werribee, Victoria 3030, Australia Philip J. Cooper Department of Infectious Diseases, St George s Hospital Medical School, Cranmer Terrace, Tooting, London SW17 ORE, UK and Laboratorio de Investigacion, Hospital Pedro Vicente Maldonado, Pedro Vicente Maldonado, Pichincha Province, Ecuador Helen Faulkner School of Life and Environmental Sciences, University of Nottingham, Nottingham, NG7 2RD, UK Robin E. Gasser Department of Veterinary Science, The University of Melbourne, Werribee, Victoria 3030, Australia Helen Guyatt Wellcome Trust Research Laboratories-Kenya Medical Research Institute, PO Box 43640, Nairobi, Kenya and Centre for Tropical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX1 3QU, UK. J. M. Hawdon Department of Microbiology and Tropical Medicine, George Washington University, Washington, D.C., USA Celia Holland Department of Zoology, Trinity College, Dublin 2, Ireland Peter J. Hotez Department of Microbiology and Tropical Medicine, George Washington University, Washington, D.C., USA

x Gregers Jungersen Danish Veterinary Laboratory, Bülowsvej 27, DK-1790 Copenhagen V, Denmark Malcolm W. Kennedy Division of Environmental and Evolutionary Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Graham Kerr Building, Glasgow G12 8QQ, Scotland Jane Kvalsvig School of Anthropology, Psychology and the Centre for Social Work, University of Natal, Durban, South Africa. Antonio Montresor Parasitic Diseases and Vector Control, World Health Organization, 1211 Geneva 27, Switzerland Susan E. Newton Victorian Institute of Animal Science, Attwood, Victoria 3049, Australia David I. Pritchard Boots Science Building, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK Rupert J. Quinnell School of Biology, University of Leeds, UK Helen Roberts Laboratory of Evolutionary Genetics, Department of Biology, UCL, London NW1 2HE, UK Lorenzo Savioli Parasitic Diseases and Vector Control, World Health Organization, 1211 Geneva 27, Switzerland Lani S. Stephenson Division of Nutritional Sciences, Savage Hall, Cornell University, Ithaca, NY 14853 USA Anita H. J. van den Biggelaar Department of Parasitology, Leiden University Medical Center, Albinusdreed 2, 2333 ZA Leiden, The Netherlands Derek Wakelin School of Life and Environmental Sciences, University of Nottingham, Nottingham, NG7 2RD, UK Sarah Williams-Blangero Department of Genetics, South West Foundation for Biomedical Research, San Antonio, Texas 78245-0549, USA Maria Yazdanbakhsh Department of Parasitology, Leiden University Medical Center, Albinusdreed 2, 2333 ZA Leiden, The Netherlands Xingquan Zhu Department of Veterinary Science, The University of Melbourne, Werribee, Victoria 3030, Australia

PREFACE The soil-transmitted nematode parasites, or geohelminths, are socalled because they have a direct life cycle, which involves no intermediate hosts or vectors, and are transmitted by faecal contamination of soil, foodstuffs and water supplies. They all inhabit the intestine in their adult stages but most species also have tissue-migratory juvenile stages, so the disease manifestations they cause can therefore be both local and systemic. The geohelminths together present an enormous infection burden on humanity. Those which cause the most disease in humans are divided into three main groupings, Ascaris lumbricoides (the large roundworm), Trichuris trichiura (whipworm), and the blood-feeding hookworms (Ancylostoma duodenale and Necator americanus ), and this book concentrates on these. These intestinal parasites are highly prevalent worldwide, A. lumbricoides is estimated to infect 1471 million (over a quarter of the world s population), hookworms 1277 million, and T. trichiura 1049 million. The highly pathogenic Strongyloides species might also be classified as geohelminths, but they are not dealt with here because the understanding of their epidemiology, immunology and genetics has not advanced as rapidly as for the others. This is primarily because of the often covert nature of the infections, with consequent difficulties for analysis. If there is ever a second edition of this book, then there will hopefully be much to say about this infection. Despite the considerable numbers of geohelminth infections, the public health perception has traditionally been that these intestinal parasites contribute comparatively little to overt disease. That perception has changed through new understanding of the parasites epidemiology and their contribution to covert chronic disease conditions. For instance, the numbers of worms recovered from populations of hosts exhibit an overdispersed or aggregated distribution most hosts harbour few or no worms whereas a small proportion of hosts carry very heavy burdens. These heavily infected individuals are therefore important from a public health perspective because they represent the main source of infection, but probably also represent the clinically most affected subpopulation. The manifestations of severe disease include fatal intestinal obstruction or pulmonary allergic reactions in ascariasis, severe anaemia in hookworm infections, and chronic dysentery and rectal prolapse in trichuriasis. Evidence has also accumulated that moderate infections of intestinal nematodes contribute significantly to chronic conditions such as growth retardation, which regresses after

xii treatment. An even more insidious and alarming effect upon cognitive development has been suggested by a growing number of intervention studies, and a recent focus upon the interrelationships between intestinal nematodes and other microparasitic diseases has revealed further potential benefits of large scale de-worming programmes. So, there is still a great need to understand more fully the true cumulative impact of these infections. Chemotherapy still remains the most effective way of reducing the intensity of geohelminth infections so as to decrease the associated morbidity and mortality. The anthelmintic drugs currently available for the treatment of human intestinal parasites are relatively safe and effective, and evidence for the development of resistance to these drugs is still scarce, although there is clearly no room for complacency given the development of resistance to similar drugs against nematodes of veterinary importance. For the moment, however, there is little to say about drug development and the development of resistance as far as human geohelminths are concerned, so the subject is not dealt with here with any emphasis. The development of new drugs is essential, but, sadly, advances are more likely to come through the veterinary imperative than from human medicine for brutal market force reasons. The understanding of epidemiological patterns has contributed to new approaches to control. For example, age-targeted chemotherapy of children focuses upon those individuals with the highest worm burdens in the community and those most at risk from developmental morbidity. An added advantage has been that children can be treated at school, thereby increasing the cost-effectiveness of treatment programmes. Moreover, a broad-spectrum approach is being considered whereby simultaneous treatment for lymphatic filariasis and intestinal nematodes is employed. Economic analysis is now an important tool used to assess the cost of infection (in terms of morbidity, lost productivity and lost human potential) and the cost of intervention, and the development of cost-effective programmes is essential for any progress to be made in developing countries in which the budgets available for healthcare are small. Another important concept in intestinal nematode biology is that of predisposition. For an individual host, worm burden does not show a random pattern upon reinfection, but exhibits consistency in the re-acquisition of low and high worm burdens. The mechanisms behind this phenomenon are likely to be multiple and it has proved difficult to unravel their relative contributions under field conditions in humans. The use of a number of different animal models and, in particular, the recently described Ascaris predisposition pig model, are likely therefore to be particularly illuminating, particularly now that the gap between laboratory animal experimentation and

xiii work on humans is closing. For instance, a recent human pedigree study has revealed evidence for a strong genetic component in the observed variation in Ascaris worm burden from person to person, and host genetics are also being examined in a variety of mouse models. Further analysis of both mice and men will hopefully soon reveal precisely which genes are involved in endowing susceptibility or resistance to intestinal nematode infections. Furthermore, the genetics of the parasites also requires understanding, both in terms of strains, geographical variation, and even at the household level. The immune response of the host to intestinal parasites has received considerable attention and, although an understanding of the individual responses mounted by the host has improved, the protective role of the different effector mechanisms is still less well understood. In particular, the relationship between infection, the production of IgE and the manifestations of atopy requires further exploration, as does the balance between immunemediated resistance to infection and immunopathology. Parasitic nematodes, Ascaris in particular, are renowned for their elicitation of powerful IgE and T helper type 2 (Th2) responses, and how these (or their absence) relate to allergic reactions is currently a focus of research, particularly in view of the dramatic increase in allergies over recent decades. The most illuminating recent studies in this regard come from immunoepidemiological studies on filariasis and schistosomiasis in humans. We have, therefore, taken the (perhaps rash) step of including a chapter on these aspects from the perspective of schistosomiasis (neither a nematode, nor intestinal!), which we argue will greatly contribute to the debate and provide direction for similar future studies on geohelminths and atopy/allergy. In summary, intestinal nematode infections are an important, prevalent and preventable public health problem, which contribute to considerable human debilitation worldwide. The challenge of their control lies in the need to raise awareness of their morbid effects and to find cost-effective and operationally realistic ways of treating the populations that are infected by them. Furthermore, aspects of their biology provide the opportunity to investigate important fundamental processes including the genetic basis of susceptibility to chronic infectious diseases and their relationships with other diseases like HIV/AIDS. Simultaneous studies on human hosts living in endemic areas and the use of appropriate animal models will help to unravel these complex host-parasite relationships. The literature on all aspects of geohelminth infections is extensive, and the purpose of this book is not to review the field comprehensively, but to present chapters by selected experts, who were asked to review a particular area and to take a prospective view in order to identify new and emerging

xiv approaches and ideas. The understanding of the genetics, epidemiology and immunology of intestinal helminths has taken dramatic leaps forward over the past decade, and we hope that this book will contribute to a wider understanding and stimulate further development of the field for both practical and theoretical purposes. Celia Holland Malcolm Kennedy Dublin and Glasgow July 2001

ACKNOWLEDGEMENTS We are compelled to extend our particular thanks to Marina Pearson, Zoology Department, Trinity College, Dublin, for her superb help and skills in formatting and collating the manuscripts, Alison Boyce, also of the Zoology Department, for excellent technical assistance with the figures, and Joanne Tracy and Dianne Wuori of Kluwer Academic Publishers for editorial support and guidance.