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This book will be invaluable to advanced undergraduates and masters students as well as PhD studentswho are beginning their graduate research project in an area of immunoparasitology.

A companion website with additional resourcesis available at www.wiley.com/go/lamb/immunity

Cover design by Dan Jubb

Parasitic infections remain a significant cause of morbidity and mortality in the world today. Often endemic in developing countries, many parasitic diseases are neglected in terms of researchfunding and much remains to be understood about parasites and the interactions they have with the immune system. This book examines current knowledge about immune responses to parasiticinfections affecting humans, including interactions that occur during co-infections, and how immuneresponses may be manipulated to develop therapeutic interventions against parasitic infection.

For easy reference, the most commonly studied parasites are examined in individual chapters written byinvestigators at the forefront of their field. An overview of the immune system, as well as introductionsto protozoan and helminth parasites, is included to guide background reading. A historical perspectiveof the field of immunoparasitology acknowledges the contributions of investigators who have beeninstrumental in developing this field of research.

Editor

TRACEY J LAMB, Emory University School of Medicine, USA

• Written by investigators at the forefront of the field

• Includes a glossary of terms for easy reference

• Illustrated in full-colour throughout

• Features separate sections on co-infection, applied parasitology and the development of vaccines against parasitic infections

I M M U N I T YT O

P A R A S I T I CI N F E C T I O N

Editor TRACEY J LAMB

Immunity to ParasiticInfection

Immunity to ParasiticInfection

Edited by

Tracey J. LambEmory University School of Medicine, USA

A John Wiley & Sons, Ltd., Publication

This edition first published 2012 ©2012 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Immunity to parasitic infection / edited by Tracey Lamb.p. ; cm.

Includes bibliographical references and index.ISBN 978-0-470-97247-2 (hardback) – ISBN 978-0-470-97248-9 (pbk.)I. Lamb, Tracey.[DNLM: 1. Parasitic Diseases–immunology. 2. Immune System–physiology.

3. Immunity–physiology. 4. Parasitic Diseases–therapy. WC 695]616.9′6071–dc23

2012023208

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print maynot be available in electronic books.

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http://www.wiley.com/wiley-blackwell

Contents

List of Contributors xiii

Introduction: Immunoparasitology: The Making of a ModernImmunological science 1Alan Sher

Section 1

1 Notes on the Immune System 15Tracey J. Lamb

1.1 The immune system 151.2 Innate immune processes 171.3 The complement cascade 191.4 Innate recognition 201.5 Pattern recognition receptors 211.6 Innate immune cells 231.7 Communication in the immune system 311.8 Adaptive immunity 311.9 The role of the MHC in the immune response 341.10 T cell activation and cellular-mediated immunity 361.11 B cells and the humoral response 431.12 Cell trafficking around the body 491.13 Cellular immune effector mechanisms 501.14 Hypersensitivity reactions 52References for further reading 54

Section 2

2 Introduction to Protozoan Infections 61David B. Guiliano and Tracey J. Lamb

2.1 The protozoa 612.2 Amoebozoa 622.3 Excavata 672.4 Harosa 752.5 Protozoa that are now fungi 812.6 Taxonomy and the evolution of the parasitic protozoa 822.7 Genomic and post genomic exploration of protozoan biology 83

vi Contents

2.8 Summary 872.9 General information on protozoa 88References for further reading 88

3 Apicomplexa: Malaria 91Tracey J. Lamb and Francis M. Ndung’u

3.1 Malaria 913.2 Recognition of malaria parasites 943.3 Innate effector mechanisms 953.4 Adaptive immunity 983.5 Memory responses 1013.6 Immune evasion 1013.7 Immunopathology 103References for further reading 105

4 Apicomplexa: Toxoplasma gondii 107Emma Wilson

4.1 Introduction 1074.2 Life cycle and pathogenesis 1074.3 Innate immune responses 1114.4 Evasion strategies 1134.5 Adaptive immune responses 1154.6 CNS infection 1174.7 Conclusions 118References for further reading 118

5 Apicomplexa: Cryptosporidium 121Jan R. Mead and Michael J. Arrowood

5.1 Life cycle 1225.2 Clinical presentation 1235.3 General immune responses in cryptosporidiosis 1245.4 Innate effector mechanisms 1255.5 Adaptive immunity 1275.6 Memory responses 1315.7 Antigens eliciting the immune response 1325.8 Immune evasion 1325.9 Immunopathology in the gut and intestinal tract 134References for further reading 134

6 Diplomonadida: Giardia 139Steven Singer

6.1 The life cycle and pathogenesis of Giardia infection 1396.2 Recognition of Giardia by the immune system 1416.3 Innate effector mechanisms against Giardia 1426.4 Adaptive immunity against Giardia 1436.5 Memory responses 1456.6 Antigens eliciting the immune response 1466.7 Immune evasion 147

Contents vii

6.8 Immunopathology 1486.9 Summary 150References for further reading 150

7 Kinetoplastids: Leishmania 153Ingrid Müller and Pascale Kropf

7.1 The pathogenesis of Leishmania infection 1537.2 Life cycle 1547.3 Parasite transmission and avoidance of immune responses 1557.4 Innate effector mechanisms: the role of neutrophils in

Leishmania infection 1577.5 Adaptive immunity: lessons from L. major infections of mice 1587.6 Arginase promotes Leishmania parasite growth 1627.7 Memory responses 163References for further reading 164

8 Kinetoplastids: Trypanosomes 165Jeremy Sternberg

8.1 The African trypanosomes (Trypanosoma brucei ssp.) 1658.2 Pathogenesis of sleeping sickness 1678.3 Variant surface glycoprotein – the key to trypanosome-host

interactions 1688.4 The humoral response to African trypanosomes 1728.5 T cell responses in African trypanosome infections 1738.6 Innate defence mechanisms: trypanosome lytic factor 1738.7 Immunopathology and VSG 1748.8 Summary 175References for further reading 176

9 Kinetoplastids: Trypanosoma cruzi (Chagas disease) 179Rick Tarleton

9.1 Life cycle and transmission 1809.2 Immune control and disease 1819.3 Innate recognition of T. cruzi 1829.4 Adaptive immunity 1839.5 Regulation of immune responses and parasite persistence 1869.6 Conclusions 189References for further reading 189

Section 3

10 Introduction to Helminth Infections 195David B. Guiliano

10.1 Acanthocephala 19610.2 Nematodes 19610.3 Pentastomida 20310.4 Platyhelminthes 20310.5 The evolution of parasitism within the helminths: divergent

phyla with common themes 208

viii Contents

10.6 Genomic and post-genomic exploration of helminthbiology 211

10.7 Summary 211References for further reading 213

11 Nematoda: Filarial Nematodes 217Sabine Specht and Achim Hoerauf

11.1 The life cycle and pathogenesis of filarial nematodeinfections 217

11.2 Animal models of filariasis 22011.3 Immune responses mounted against filarial nematodes 22111.4 Innate immunity 22111.5 Adaptive immunity 22411.6 Immune evasion 22511.7 Immunopathology 228References for further reading 229

12 Nematoda: Ascaris lumbricoides 231Christina Dold

12.1 Introduction 23112.2 Ascaris infection displays an over-dispersed frequency

distribution 23212.3 Life cycle 23212.4 Pathogenesis of infection 23312.5 Animal models of Ascaris infection 23412.6 Immune responses generated against the migratory phase

of Ascaris 23512.7 The cytokine response to Ascaris lumbricoides 23712.8 The humoral response to Ascaris lumbricoides 23812.9 Antigens eliciting immune responses in Ascaris infection 24112.10 Conclusions 242References for further reading 243

13 Nematoda: Hookworms 247Soraya Gaze, Henry McSorley and Alex Loukas

13.1 Pathogenesis of hookworm infection 24713.2 The life cycle of hookworms 24813.3 Animal models of hookworm infection 24913.4 Innate immune responses to hookworms 25113.5 Adaptive immunity 25213.6 Cytokine responses 25313.7 Antibody responses 25413.8 Antigens eliciting the immune response 25513.9 Memory responses 25513.10 Immunoregulatory aspects of the anti-hookworm immune

response 25613.11 Conclusion 258References for further reading 259

Contents ix

14 Nematoda: Trichuris 263Colby Zaph

14.1 Trichuris infection 26314.2 Life cycle and pathogenesis 26414.3 Immunity to Trichuris 26514.4 Recognition by the immune system 26514.5 Innate immune responses 26514.6 Adaptive immune responses 26914.7 Immune memory 26914.8 Vaccines 27014.9 Trichuris as a therapeutic 27014.10 Summary 271References for further reading 271

15 Nematoda: Trichinella 275Judith A. Appleton, Lisa K. Blum and Nebiat G. Gebreselassie

15.1 Life cycle 27515.2 Pathogenesis 27715.3 Adaptive immunity 27815.4 Immunopathology 28215.5 Evasion strategies 283References for further reading 284

16 Trematoda: Schistosomes 287Mark Wilson

16.1 The schistosome life cycle 28716.2 Immunological recognition of schistosomes 29016.3 Innate effector mechanisms 29116.4 Adaptive immunity 29216.5 Memory responses 29716.6 Schistosome antigens eliciting immune responses 29816.7 Immune evasion 29816.8 Schistosomiasis and immunopathology 299References for further reading 303

17 Cestoda: Tapeworm Infection 307César A. Terrazas, Miriam Rodrı́guez-Sosa and Luis I. Terrazas

17.1 The life cycle of tapeworms 30717.2 Epidemiology 30917.3 Pathology 31017.4 Innate immunity 31117.5 Adaptive immunity 31217.6 Antigens eliciting the immune responses 31517.7 Immunomodulation or evasive mechanisms 31617.8 Echinococcosis 31617.9 Conclusions 320References for further reading 320

x Contents

Section 4

18 Co-infection: Immunological Considerations 325Joanne Lello

18.1 Co-infection is the rule rather than the exception 32518.2 Interactions between co-infecting parasites 32618.3 The Th1/Th2 paradigm in co-infection 32718.4 Co-infection can alter disease severity 32818.5 Modelling parasite interactions during co-infection 32918.6 Co-infection as a therapy? 33018.7 Consideration of co-infection in an ecological framework 33118.8 Concluding remarks 332References for further reading 333

19 HIV and Malaria Co-infection 335Aubrey Cunnington and Eleanor M. Riley

19.1 The endemicity of HIV and malaria 33519.2 HIV infection 33519.3 Immunopathogenesis of HIV 34119.4 Interactions between malaria and HIV 34319.5 Effect of co-infection on treatment of HIV and malaria

infections 34719.6 Combined effects of HIV and malaria on susceptibility to

other diseases 34819.7 Malaria and HIV vaccines 34919.8 Summary 351References for further reading 351

20 HIV and Leishmania Co-infection 353Javier Moreno

20.1 Leishmania parasitaemia is increased in HIV-Leishmaniaco-infection 354

20.2 Leishmania infection increases viral replication rate 35420.3 Cell specific interactions between HIV-1 and Leishmania 35520.4 Immune response interactions between HIV-1 and

Leishmania 35720.5 Immune reconstitution inflammatory syndrome in

HIV-1/Leishmania co-infection 358References for further reading 359

21 Gastrointestinal Nematodes and Malaria 361Mathieu Nacher

21.1 Introduction 36121.2 Results from field studies in humans are conflicting 36121.3 Immune responses in GI nematode and malaria

co-infections 36321.4 Stereotypical but different 37021.5 Animal models of GI nematode-malaria co-infection 37021.6 Conclusions 372References for further reading 372

Contents xi

22 Malaria and Schistosomes 375Shona Wilson and Jamal Khalife

22.1 The epidemiology of schistosomiasis and malariaco-infection 375

22.2 Study design for malaria/schistosome co-infectionstudies 376

22.3 Antibody responses 38022.4 Cytokine responses 38222.5 Contribution of experimental models to the

understanding of Schistosoma mansoni andPlasmodium co-infection 384

22.6 Conclusions 385References for further reading 385

Section 5

23 Hygiene and Other Early Childhood Influences on theSubsequent Function of the Immune System 391Graham A.W. Rook

23.1 Introduction 39223.2 The Hygiene Hypothesis (or ‘Old Friends’ hypothesis) 39223.3 Epidemiological transitions 39323.4 Compensatory genetic variants 39423.5 The critical organisms and their immunological role 39523.6 Helminth infections and allergic disorders 39523.7 Helminths and non-allergic chronic inflammatory

disorders: human data 39623.8 Animal models of helminth infection used to test the

Hygiene Hypothesis 39723.9 Non-helminthic ‘Old Friends’ 39723.10 Mechanisms of immunoregulation 39823.11 Conclusions 399References for further reading 400

24 Nematodes as Therapeutic Organisms 401William Harnett and Margaret M. Harnett

24.1 Evidence that parasitic nematodes can protect humansfrom allergy and autoimmunity 401

24.2 Mechanism of action 40424.3 Nematode molecules involved in preventing

allergic/autoimmune disease 40824.4 Clinical aspects 412References for further reading 413

25.1 Vaccination Against Malaria 417Alberto Moreno

25.1.1 Malaria vaccines: proof of concept 41725.1.2 Vaccine development 41925.1.3 Pre-erythrocytic vaccines 420

xii Contents

25.1.4 Erythrocytic vaccines 42325.1.5 Transmission-blocking vaccines 42525.1.6 Whole organism vaccines 42625.1.7 P. vivax vaccines 42725.1.8 Concluding remarks 429References for further reading 429

25.2 Current Approaches to the Development of a Vaccine AgainstLeishmaniasis 431Yasuyuki Goto and Steven G. Reed

25.2.1 Vaccination against leishmaniasis 43225.2.2 Anti-amastigote vaccines 43225.2.3 Anti-saliva vaccines 43625.2.4 Transmission prevention vaccines 43625.2.5 Role of an adjuvant in vaccine development 43625.2.6 Future directions 438References for further reading 438

25.3 Vaccination Against Hookworms 441Brent Schneider, Maria Victoria Periago and Jeffrey M. Bethony

25.3.1 The need for a vaccine 44125.3.2 The Human Hookworm Vaccine Initiative 44225.3.3 The history of hookworm vaccines: experiments in dogs 44325.3.4 Antibody production against canine hookworm 44325.3.5 Vaccination against hookworm with irradiated larvae 44425.3.6 Lessons from vaccination with irradiated larvae 44525.3.7 Research identifying target proteins for an

anti-hookworm vaccine 44625.3.8 A human hookworm vaccine phase 1 clinical trial based

on Na-ASP2 45325.3.9 The HHVI takes a different approach 45425.3.10 Developments through the last century and the future 455References for further reading 456

25.4 Current Approaches to the Development of a Vaccine AgainstFilarial Nematodes 459Sara Lustigman

25.4.1 Introduction to anti-filarial nematode vaccines 45925.4.2 Anti-O. volvulus and anti-LF vaccines are a valid

approach to advance control measures againstonchocerciasis and lymphatic filariasis 461

25.4.3 Future directions for vaccine development 46625.4.4 Discovery of new vaccine candidates 467References for further reading 468

Abbreviations 471

Glossary 479

Index 493

List of Contributors

Tracey J. Lamb (Editor)Department of Pediatrics, Emory University School of Medicine, 2015 Upper-gate Drive, Atlanta, Georgia 30322, USA.

Judith A. AppletonBaker Institute for Animal Health, College of Veterinary Medicine, CornellUniversity, Hunderford Hill Road, Ithaca, NY 14853, USA.

Michael ArrowoodDivision of Foodborne, Waterborne and Environmental Diseases, Centers forDisease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333, USA.

Jeffrey M BethonyDepartment of Microbiology, Immunology and Tropical Medicine, GeorgeWashington University Medical Center, Washington DC, USA.

Lisa K. BlumBaker Institute for Animal Health, College of Veterinary Medicine, CornellUniversity, Hunderford Hill Road, Ithaca, NY 14853, USA.

Aubrey CunningtonLondon School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK.

Christina DoldOxford Vaccine Group, Oxford University, Department of Pediatrics, Centre forClinical Vaccinology and Tropical Medicine, Churchill Hospital, Headington,Oxford, OX3 7LJ, UK.

Soraya GazeQueensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878,Australia.

Nebiat G. GebreselassieBaker Institute for Animal Health, College of Veterinary Medicine, CornellUniversity, Hunderford Hill Road, Ithaca, NY 14853, USA.

Yasuyuki GotoLaboratory of Molecular Immunology, Graduate School of Agricultural and LifeSciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657,Japan.

xiv List of Contributors

David B. GuilianoSchool of Health, Sport and Bioscience, University of East London, StratfordCampus, London, E15 4LZ, UK.

Margaret M. HarnettInstitute of Infection, Immunity and Inflammation, Glasgow Biomedical Re-search Centre, 120 University Place, University of Glasgow, Glasgow, G128TA, UK.

William HarnettStrathclyde Institute of Pharmacy and Biomedical Sciences, University ofStrathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow, G40NR, UK.

Achim HoeraufInstitute of Medical Microbiology, Immunology and Parasitology, UniversityClinic Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.

Jamal KhalifeCentre for Infection and Immunity of Lille INSERM, U1019-CNRS UMR 8204,University Lille Nord de France, Institute Pasteur de Lille, 1, Rue du ProfesseurCalmette, 59019 Lille Cedex, France.

Pascale KropfLondon School of Hygiene and Tropical Medicine, Immunology and InfectionDepartment, Keppel Street, London, WC1E 7HT, UK.

Joanne LelloCardiff School of Biosciences, The University of Cardiff, Biomedical SciencesBuilding, Museum Avenue, Cardiff, CF10 3AX, Wales, UK.

Alex LoukasQueensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878,Australia.

Sara LustigmanLaboratory of Molecular Parasitology, Lindsley F. Kimball Research Institute,New York Blood Center, New York, NY 10065, USA.

Henry McSorleyQueensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878,Australia.

Jan MeadDepartment of Pediatrics, Emory University School of Medicine, Atlanta VAMedical Center, 1670 Clairmont Road, Dectaur, GA 30033, USA.

Alberto MorenoEmory Vaccine Center, Yerkes National Primate Research Center, Division ofInfectious Diseases, Department of Medicine, Emory University, 954 GatewoodRoad, Atlanta, Georgia 30329, USA.

List of Contributors xv

Javier MorenoNational Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda(Madrid), Spain.

Ingrid MüllerDepartment of Medicine, Section of Immunology, Faculty of Medicine, ImperialCollege London, UK.

Mathieu NacherEquipe EA 35 93, Epidémiologie des parasitoses et mycoses tropicales, Univer-sité Antilles Guyane, Campus Saint Denis, Cayenne, French Guiana.

Francis M NdunguKenya Medical Research Institute, KEMRI-Wellcome Programme, P.O. Box230–80108, Kilife, Kenya.

Maria Victoria PeriagoInstituto René Rachou, Belo Horizonte, Minas Gerais, Brazil.

Steven G. ReedInfectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle,WA 98104, USA.

Eleanor M. RileyLondon School of Hygiene and Tropical Medicine, Keppel Street, London,WC1E 7HT, UK.

Miriam Rodrı́guez-SosaUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universi-dad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes IztacalaTlalnepantla, Edo. México, 54090 México.

Graham RookCentre for Infectious Diseases and International Health, Windeyer Institute forMedical Sciences, University College London (UCL), London, WIT 4JF, UK.

Brent SchneiderDepartment of Microbiology, Immunology and Tropical Medicine, GeorgeWashington University Medical Center, Washington DC, USA.

Alan SherNational Institute for Allergy and Infectious Diseases, Bldg. 50, Rm. 6140, MSC8003, Bethesda, MD 20892, USA.

Steven SingerDepartment of Biology and Center for Infectious Disease, Georgetown Univer-sity, Washington, DC 20057–1229, USA.

Sabine SpechtInstitute of Medical Microbiology, Immunology and Parasitology, UniversityClinic Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.

xvi List of Contributors

Jeremy SternbergSchool of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK.

Rick TarletonUniversity of Georgia – CTEGD, 145 Coverdell Centre, 500 D.W. Brooks Drive,Athens, GA 30602-7399, USA.

César A. TerrazasUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universi-dad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes IztacalaTlalnepantla, Edo. México, 54090 México.

Luis I. TerrazasUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universi-dad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes IztacalaTlalnepantla, Edo. México, 54090 México.

Emma WilsonDivision of Biomedical Sciences, University of California – Riverside, Riverside,CA 92521, USA.

Mark WilsonDepartment of Molecular Immunology, National Institute for Medical Re-search, The Ridgeway, Mill Hill, London, NW7 1AA, UK

Shona WilsonDivision of Microbiology and Parasitology, Department of Pathology, Universityof Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.

Colby ZaphThe University of British Columbia, The Biomedical Research Centre, De-partment of Pathology and Laboratory Medicine, 2222 Health Sciences Mall,Vancouver, BC, V6T 1Z3, Canada.

IntroductionImmunoparasitology: the

making of a modernimmunological science

Alan Sher, PhDNational Institute for Allergy and Infectious Diseases, Bethesda, USA

The field of immunoparasitology has developed from a subspecialty of par-asitology into a dynamic immunological discipline with its own unique in-tellectual territory and conceptual contributions. Much of this evolution hasoccurred in recent times. Indeed, the word ‘immunoparasitology’ only cameinto common usage in the last 40, years appearing in the Merriam WebsterDictionary as ‘a branch of immunology that deals with animal parasites andtheir hosts’. It is significant that the lexicographer who provided this definitiongrasped that immunoparasitology was now in the realm of the immunologistand no longer a discipline practised primarily by parasitologists. In this intro-ductory chapter, I will briefly trace the history of our field and highlight theimportant influence that research in immunoparasitology has had on modernimmunological thought.

Origins

In considering the origins of immunoparasitology, one is immediately con-fronted with the issue of why the study of parasitology selectively deals withhelminths, protozoa and ectoparasites. Although all of these agents were ini-tially classified as eukaryotes, this definition now makes little taxonomic sense,as pathogenic fungi which are also eukaryotes are not referred to as parasites.Moreover, several parasitic unicellular organisms with primitive genomes (e.g.Giardia and microporidia) which were formerly thought to be protozoa haveeither been reclassified as fungi and/or been given the more general desig-nation of ‘protists’ due to their unclear evolutionary status (see Chapter 2).Clearly, the original classification of protozoa and helminths as parasites was

Immunity to Parasitic Infection, First Edition. Edited by Tracey J. Lamb.C© 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

2 Introduction

a historical invention, which likely reflected not only their unusual taxonomybut also, perhaps, their identity as common and widespread disease agents ofthe tropics.

Given this artificial taxonomic classification which came into common usagein the 19th century, one can reach back earlier in history for examples of whenhost resistance phenomena concerning pathogens now known as parasiteswere first recognised. Human cutaneous leishmaniasis (Chapter 7) is a likelycandidate, because it has been known since ancient times that individuals whohad healed their skin lesions were protected from further infections. For thisreason, Bedouin or some Kurdistani tribal societies traditionally exposed in-fants to sandfly bites in order to protect them from parasite mediated faciallesions later in life.

Another ancient form of immunisation against leishmaniasis, described inwritten records from 10th century Persia, is the use of a thorn to transfer infec-tious material from lesions to uninfected individuals. Ironically, this practice of‘leishmanisation’, in which humans are inoculated with live, unattenuated or-ganisms that produce self-healing infections, remains the only truly effectiveprocedure for vaccination against parasitic pathogens, although it is now sel-dom used (Chapter 25.2). Acquired resistance to ‘swamp fever’ (malaria) wasalso recognised by European colonisers of tropical countries, who came to re-alise their extreme susceptibility relative to that of the indigenous populations.This, too, was an unwitting exercise in immunoparasitological thought.

The era in which most of the major parasitic infections of man were defined(i.e. the second half of the 19th century and the early 20th) coincided with theage in which the role of the immune system in host defence was first eluci-dated. While others may deserve consideration for the title of first modern im-munoparasitologist, Robert Koch, the great German microbiologist, is a promi-nent candidate (Figure 1). Using newly developed techniques for identifyingmalaria parasites stained in blood films, Koch compared the frequency anddensity of parasitaemia in two distinct populations in Java with either high orlow endemicity. The conclusion of this cross-sectional analysis was that protec-tion against malaria is acquired only after heavy and repeated exposure to theparasite. These early observations were soon confirmed and extended by otherinvestigators, who described the basic features of naturally acquired immunityto malaria in man, in part through the later use of live malaria infection to treatneurosyphilis. Although recognised earlier than protozoa as human parasites,the existence of acquired immunity to helminths was less obvious and awaitedthe next phase in the development of the field.

Development of immunoparasitology as anexperimental science

As the life cycles of the major parasitic infections of humans and livestockwere elucidated, scientists began to question the involvement of the immuneresponse in determining the nature of the host-parasite interaction, as well

Immunity to Parasitic Infection 3

Figure 1 Some pioneers and early champions of the field of immunoparasitology.

as considering the possible use of vaccination as an intervention strategy inparasitic diseases. Two American scientists, Norman Stoll and William Talia-ferro, who produced most of their important work in between the two WorldWars, were leading figures in this new research effort.

� Stoll (1892–1976), considered by many to be the father of quantitativehelminthology, challenged the dogma of his time that argued that wormsfail to induce immunity. He did so by documenting the phenomena of self-cure and acquired resistance in farm and experimental animals infectedwith gastrointestinal helminths, and he went on to perform vaccination tri-als with parasite extracts.

� Taliaferro (1895–1973) was Stoll’s counterpart in protozoan immunology.Together with his wife Lucy, he conducted experimental infections with try-panosomes and malaria in rodents, documenting both acquired immunityand the role of antibodies in protection against parasite variants.

4 Introduction

The work of these American pioneers (performed largely at Johns Hopkins,Rockefeller and Princeton) thus demonstrated the existence of immunologi-cal resistance to protozoan and helminth infection and revealed the power ofanimal models in studying the immune response to parasitic pathogens.

The immunological renaissance

The 1960s and 1970s saw an explosion of interest in parasite immunology. Thisresponse was fuelled by two important developments of that era. The first wasthe highly optimistic (and, in retrospect, quite short-sighted) sentiment thatmost other major infectious disease problems could be contained and eveneradicated by the vaccines, drugs, and vector control measures that were be-ing deployed successfully in many settings at that time. This attitude was epit-omised in the statement attributed to the then Surgeon General of the UnitedStates, William Stewart, that: “It is time to close the book on infectious diseases,and declare the war against pestilence won.”

This bold conclusion, however, clearly did not apply to parasitic diseases, whichthen continued to represent a global scourge, with no vaccines and a limitednumber of partially effective and often toxic drugs. For this reason, leaders inthe infectious disease community advocated new funding initiatives for the de-velopment of intervention strategies for parasitic infection, referring to it as thelast frontier for the field.

A key figure in this effort was Kenneth Warren, a schistosomiasis researcher,who, at the Rockefeller Foundation, built an influential international networkof grantees known as ‘The Great Neglected Diseases of Mankind’ (or GND forshort). Warren also attracted other private foundations (e.g. Edna McConnellClark, Macy, McArthur) to the field. Warren was himself an immunologist, andmany of the investigators he enlisted in the GND programme (e.g. GrahamMitchell, Hans Wigzell, John David, Peter Pearlman, Gus Nossal) were leadersin that field.

The second major development that fuelled the growth of immunoparasitologyin the 1970s was the rapid expansion of cellular and molecular immunologythat occurred during the same period. The major discoveries made during thisera established the cellular basis of the immune response, revealing the funda-mentals of immunological specificity and of ‘self/non-self discrimination’ andproviding powerful new tools (e.g. T cell clones and monoclonal antibodies) foridentifying antigenic targets of immune reactions.

Of critical importance were those parasitologists who were quick to realise thepotential of the ‘immunobiological revolution’ and to incorporate its new in-sights and approaches into their own research. In Britain, these scientists in-cluded Sydney Cohen and Neal Brown, who established the roles of humoralimmunity in malaria and antigenic variation as an immune evasion strategy,and Bridget Ogilvie. The latter was one of the first to investigate the parallels be-tween the immune response to helminths and allergy, and she had enormousvision in seeing the immunological lessons to be learned from studying worm

Immunity to Parasitic Infection 5

infections. Later, as Director of the Wellcome Trust, Ogilvie played a key role inpromoting the development of modern parasitology research in the UK.

Another important British investigator was James Howard, who, in addition tobuilding a highly innovative parasitology group at the Burroughs Wellcome Re-search Labs in Beckenham, UK, performed pioneering studies with FY Liew onthe function of CD4+ T cells in host resistance and susceptibility to Leishma-nia major in the murine model (Chapter 7). In the USA, Jack Remington playedan analogous role in establishing the critical function of cell-mediated immu-nity in host resistance to Toxoplasma infection (Chapter 4). These transitionalpioneers helped open up the field of parasitology to modern immunologicalapproaches and laid the groundwork for the major discoveries of the followingdecades.

Early breakthroughs and disappointments in parasitevaccine development

In addition to the advent of new tools, such as monoclonal antibodies for iden-tifying targets of the immune response, the late 1970s and 1980s saw the devel-opment of powerful technology for cloning and expressing pathogen proteins.In the case of parasites, these approaches first came together in the devel-opment of protective monoclonal antibodies (mAb), recognising the circum-sporozoite protein (CSP) of malaria by Ruth Nussenzweig, and the cloning,sequencing and expression of this major vaccine antigen (Chapter 25.1) byseveral groups in the early 1980s. This was a major achievement for the field,and it set off a wave of well-funded studies in which the same strategy wasused to identify and synthesise potential vaccine immunogens in other ma-jor parasitic pathogens. Nevertheless, despite the enormous optimism of theseprojects, in no case (including malaria CSP itself) was sufficient protectionachieved with the recombinant antigens during this era, either in experimentalor human trials, to justify further development into operational vaccines.

The widespread failure of this molecularly-based strategy for parasite vaccinedevelopment underscored the dearth of information concerning immunolog-ical effector mechanisms capable of controlling parasitic infections, and howone administers parasite antigen to specifically trigger them. These importantquestions had been largely ignored by the molecular vaccine researchers, butwere central issues for the new breed of immunoparasitologists studying thecellular immunology of parasitic infection.

Effector mechanisms and effector choicein parasitic infection

The researchers studying the basics of the immune response to parasites hadearly on focused on the identification of effector mechanisms capable of re-stricting helminth and protozoan infections. Using in vitro-grown parasitestages as targets, both antibodies and/or cells could be demonstrated to me-diate pathogen cytotoxicity or growth inhibition.

6 Introduction

An important example of such work was a study by Butterworth and colleagues,demonstrating antibody-dependent cytotoxicity against schistosome larvae byhuman eosinophils (Chapter 16). However, it soon became clear that multipleimmune mechanisms were capable of killing parasites or interfering with theirgrowth in vitro, and that what was needed was the identification of immuneresponses capable of controlling parasitic infection in vivo.

In early studies, it was recognised that helminths induce immune responsesthat are quite distinct from those induced by protozoa. Whereas worm in-fections were associated with elevated levels of IgE, eosinophilia and masto-cytosis that are manifestations of immediate-type hypersensitivity, protozoaninfections generally lacked these responses and, instead, often displayed cell-mediated immune reactions (e.g. delayed-type hypersensitivity). It was naturalto propose that these different immune effectors played important roles in hostresistance to the parasites that triggered them.

With the discovery that both immediate-type and delayed-type hypersensitivityresponses are mediated by the same T cell subpopulation defined by the pres-ence of the CD4 molecule, the field was presented with an interesting paradox.Moreover, this effector choice dichotomy was not limited to worm versus pro-tozoan infections. Thus, when certain Leishmania major strains were used toinfect BALB/c and C57BL6 mice, a similar immediate versus delayed type re-sponse dichotomy was observed, accompanied by either exacerbation or heal-ing of infection (Chapter 7).

An explanation for this effector dichotomy came with the discovery that CD4+T helper (Th) cells consist of multiple subsets defined by their cytokine secre-tion patterns, with Th1 cells producing interferon (IFN)-γ and inducing cell-mediated immunity, while Th2 cells promote immediate hypersensitivity re-sponses through the production of interleukin (IL)-4, IL-5 and IL-13.

Importantly, the immune response dichotomies seen in experimental and hu-man parasitic infection provided the first well-defined demonstrations of thein vivo relevance of this concept. Of particular importance was the murineL. major model, where healing was linked with Th1 and exacerbation of infec-tion with Th2 induction. At the same time, helminth infection was revealed tobe a potent and robustly consistent stimulus for Th2 responses, and IL-4 (and,later, IL-13) were shown to participate in resistance to gastrointestinal nema-todes. Thus, work on parasitic infection models contributed enormously to thedevelopment of the concept of immunological effector choice.

Parasites define roles for regulatory T cells

An exciting by-product of the work on CD4 T lymphocyte subsets in the L. majormodel was the discovery that Th2 cells promote infection by down-modulatingthe host protective Th1 response. At that time, the concept that CD4 T cellscould regulate immune responses was novel, as CD8+ T cells were thought tobe specifically endowed with regulatory (‘suppressor’) function. Nevertheless,the situations in which Th2 lymphocytes were found to regulate Th1 effector

Immunity to Parasitic Infection 7

function in vivo in parasitic infection were later shown to be limited to a fewmodels and. in the case of L. major, to some – but not all – parasite isolates.

However, with the discovery that CD25+Foxp3 T regulatory (Treg) cells play amajor role in dampening immune responses, it became clear that this CD4+T cell subset has a more generalised function in regulating host resistance tomicrobes. Once again, many of the pioneering in vivo observations supportingthis concept were made in parasitic infection models of mice. As discussed be-low, studies on parasitic infection later led to the discovery that effector cellscan, themselves, be induced to display regulatory activity.

Parasites help define the roles of regulatory cytokines andthe plasticity of CD4+ T cell subsets

The growing interest in T cell subsets and immune regulation in parasite-infected hosts led naturally to a focus on the cytokine mediators of these func-tions. Major discoveries were made that helped define the in vivo activitiesof two cytokines in particular: IL-10 and IL-27. Although IL-10 was originallydescribed as a product of Th2 cells, we now know that it can be producedby a variety of T cell subsets, including Tregs, as well as appropriately stimu-lated myeloid cells. Early work established that IL-10 could dampen immuneresponses through its down-regulation of antigen presenting cell (principallymacrophage and dendritic cell (DC)) effector function.

However, when IL-10 deficient mice were infected with Toxoplasma gondii,they became more susceptible, rather than more resistant, to parasite-inducedmortality. This was because, in the absence of IL-10, the host mounts an un-controlled pro-inflammatory cytokine response, resulting in tissue damage andshock. In a contrasting set of studies, treatment with anti-IL-10R antibodies wasshown to trigger healing of mice chronically infected with L. major. These find-ings indicated that, while IL-10 is critical in protecting the host against parasite-induced immunopathology, its induction can promote parasite persistencein different settings. Similarly, the discovery of the in vivo anti-inflammatoryproperties of IL-27 (an IL-12 family cytokine that was originally thought to be aTh1-promoting cytokine) came from studies on infection with Toxoplasma andother parasites.

While IL-27 is produced largely by myeloid cells, T cells represent one of themajor sources of IL-10. As noted above, the suppressive effects of Treg can beattributed to IL-10. However, it was work in protozoan models that establishedfor the first time the role of Th1 cells as a biologically important source of the IL-10 that can suppress both immunopathology in T. gondii infection and promotethe survival of non-healing strains of L. major.

Interestingly, in the former situation, the same IL-10 producing cells can dis-play IFN-γ dependent effector function against the parasite, making them dualeffector-regulatory cells. In later work with the T. gondii model, the oppositesituation was also demonstrated: Treg CD4+ T cells were shown to acquire theability to produce IFN-γ as an effector cytokine. Thus, work on parasite models

8 Introduction

has contributed enormously to our understanding of the plasticity of cytokineexpression in CD4+ T cell subsets.

Parasites as triggers of the innate immune response

In approaching the problem of T helper polarisation, immunoparasitologistsdeduced that events occurring soon after parasite entry must be dictating thesubsequent choice of T cell subset induced. These events consist of specificsignals delivered by the innate immune system in response to parasite recog-nition. With the discovery that the cytokines IL-12 and IL-4 potently influenceTh1 and Th2 differentiation respectively, it made sense that the selective trig-gering of one or the other mediator by different parasites would explain theirability to mediate CD4+ T cell polarisation. Indeed, mice deficient in IL-12 orIL-4 showed greatly reduced Th1 or Th2 responses following infection with in-tracellular protozoa or helminths, respectively.

The above findings prompted a search for the cellular sources of IL-12 and IL-4in the innate immune system and the receptor on these cells that trigger cy-tokine production in response to parasite recognition. DCs, macrophages andneutrophils were documented as major sources of the Th1-polarising cytokineIL-12, and Toll-like receptors as the likely NFκ-B trigger of IL-12. However, atthe same time, it became clear that, although DCs can promote Th2 responses,this is not the result of their production of IL-4. Instead, more recent work inhelminth infection has documented a role for basophils as the source of theIL-4 involved in Th2 differentiation (Chapter 14), although there is debate as towhether the IL-4 derived from this source is actually initiating the Th2 responseor merely amplifying a Th2 population already triggered by a signal from an-other innate cellular source, such as DCs.

The study of helminth Th2 response initiation has also contributed to the re-cent discovery of novel innate lymphoid populations (collectively designatedas ILC2) that produce IL-4 and other Th2 cytokines in response to IL-25 andIL-33 stimulation and participate in worm expulsion. The parasite-host recep-tor interactions that trigger these innate Th2 signals remain to be defined, andare currently an exciting frontier in this rapidly expanding field.

Lessons from helminth immunology about allergicand fibrotic disease

As noted above, early immunoparasitologists were quick to grasp the common-alities between the immune response to worms and the allergic response andwere fascinated with the paradox of why the former is host-beneficial whilethe latter is host-detrimental. In dissecting the key immunological hallmarks ofhelminth immunity (IgE, eosinophils and mast cells/basophils), immunopara-sitologists have made major contributions to understanding their role in aller-gic tissue inflammation, along with the cytokines (e.g. IL-10, IL-13, IL-25, IL-33)and the cells (e.g. Treg, Th1) that regulate their function.

Immunity to Parasitic Infection 9

The recognition that helminth Th2 responses are carefully modulated by thehost and as a consequence trigger minimal pathology has helped promote aversion of the ‘hygiene hypothesis’ that proposes that elimination of helminthinfection as a consequence of economic development has led to a worldwideincrease in allergic disease (Chapter 23). Indeed, the field of helminth im-munology is currently enjoying a resurgence, largely based on the insights ithas provided to the role of Th2 responses in tissue sites and the mechanismof their regulation. In this context, the study of the immunopathology inducedby schistosome eggs in liver and lung (Chapter 16) has yielded important ba-sic information on Th2-driven granuloma formation and fibrosis. In the caseof the latter topic, it has also revealed major roles for IL-13 and other cytokinemediators in the fibrotic process.

Returning from mouse to man

The field of immunoparasitology has contributed to modern immunologylargely through discoveries made in murine experimental models. Neverthe-less, it is clear that, to be relevant, the concepts that have emerged must bealso be valid in humans. Since mechanistic experiments (e.g. the demonstra-tion of passive immunity in malaria by Cohen and colleagues) are feasible onlyin rare instances, the findings obtained have been gleaned largely from descrip-tive longitudinal studies on parasitic infection.

However, clever use of ethically acceptable interventional studies, for exam-ple those tracking immune responses and reinfection following chemother-apy, have yielded important insights into mechanisms of immunoregulation,host resistance and immunological memory in human parasitic disease. Withthe advent of powerful new tools, such as multifunctional flow cytometry andgene expression profiling, these studies now offer greatly increased analyt-ical depth and have expanded, particularly in the malaria field, where theanimal models for studying human P. falciparum and P. vivax infections arelimited (Chapter 3). The new developments in human cellular immunologyhave also advanced the interpretation of vaccine trials, providing correlatesof both protection and failed protection that can be analysed using systemsapproaches.

Andrade’s challenge and the future of immunoparasitology

At a schistosome vaccine meeting in the 1980s the distinguished Brazilianpathologist, Zilton Andrade made the highly quoted statement: “Schistosomi-asis has done more for immunology, than immunology for schistosomiasis.”His words were a challenge to the attendees at the conference to translate theirknowledge of the immune response directly into vaccine development, ratherthan merely using parasites to study the immune system. The issue raised byProfessor Andrade is complex, since we still lack the understanding required torationally design effective immunisation strategies protective against complexpathogens.

10 Introduction

Milestones in the history of immunoparasitology.

1900 Robert Koch’s demonstration of naturally acquired immunity in human malaria.

1920 Basic parameters of acquired immunity in malaria defined in infected populations and neurosyphilis patientsreceiving ‘malariatherapy’.

1924 William Taliaferro describes antibody-mediated control of trypanosome infection in a rat experimental model.

1927 von Wagner-Jauregg awarded Nobel Prize for malariatherapy.

1928 Norman Stoll defines phenomena of self-cure and protection in intestinal nematode infection.

1929 Taliaferro publishes landmark volume, The immunology of parasitic infections.

1961 Cohen and McGregor demonstrate passive transfer of resistance to malaria in Gambian children.

1964 Reaginic (IgE) antibodies described in helminth infection by Ogilvie

1965 Discovery of antigenic variation in malaria by Brown and Brown and classic analysis of phenomenon inAfrican trypanosomes by Gray

1967 Nussenzweig demonstrates protection against malaria mediated by irradiated sporozoites

1967 Demonstration of schistosome egg granuloma as manifestation of cell-mediated immunity by Warren, usinglung injection model developed by von Lichtenberg (1962).

1975 Eosinophils described as effector cells against schistosome larvae by Butterworth.

1980 Enhanced susceptibility of BALB mice to cutaneous Leishmaniasis demonstrated by Howard and Liew to beform of immunologic suppression mediated by CD4 T cells.

1980 Monoclonal antibodies against circumsporozoite protein (CSP) shown by Nussenzweigs to confer protectionagainst malaria.

1984–1985 Gene encoding malaria CSP cloned and sequenced by McCutchan and Godson.

1986 Th1 and Th2 subsets of CD4+ T lymphocytes identified by Mosmann and Coffman.

1987 Development of RTS,S vaccine initiated at Glaxo Smith Kline and Walter Reed.

1988–9 Opposing roles of Th1 and Th2 subsets in resistance to Leishmania described by Scott and Locksley.

1993–8 Functions of IL-12 and IL-10 in host resistance to parasitic infection elucidated by Gazzinelli, Scott, Wynn andTrinchieri.

1997–8 Initiating roles for dendritic cells in the host response to protozoan infection demonstrated by Reis e Sousaand Kaye.

1999 IL-13 revealed by Wynn to be a major determinant of helminth-induced Th2 tissue pathology and fibrosis.

2002–2007 Demonstration of roles of Treg and IL-10 producing Th1 cells in control of parasitic infection and disease byBelkaid, Sacks and Jankovic.

2003 Function of IL-27 as negative regulator of CD4+ T cell effector function in protozoan infection demonstrated byHunter.

2010 Innate lymphoid cell subsets discovered as drivers of Th2 responses in helminth infection.

2011 Partial efficacy of RTT,S vaccine against malaria confirmed in large phase three clinical trials.

Nevertheless, through successive refinements to the original concept of theNussenzweigs of immunisation with CSP, a partially effective malaria vaccinethat has now given reproducible results in multiple trials has emerged. Thisvaccine, known as RTS,S, is a recombinant protein that fuses a part of the P. fal-ciparum CSP with the hepatitis B virus surface antigen as a carrier matrix andis administered with a proprietary liposome-based adjuvant system produced

Immunity to Parasitic Infection 11

by Glaxo Smith Kline (Chapter 25.1). RTS,S is believed to function through theproduction of antibodies and T cells that inhibit hepatocyte infection and par-asite development, although the contribution of each of these mechanisms ispoorly understood. Strikingly, the improving efficacy of RTS,S is very much theproduct of empirical changes in its formulation, not the malaria Ag constructitself, which was developed over 14 years ago.

The RTS,S story, while a milestone for the field, sends a clear message for futurepriorities for the field. First, it responds to Andrade’s challenge by vindicatingthe need to understand better the immune effector mechanisms that can actagainst parasites and how best to induce them – questions that are core issuesin cellular immunology. At the same time, it points to the glaring deficiency thatwe have in immune correlates of protection in humans, as well as the need bothfor extensive further research and for the development of novel, more powerfultools for carrying out this analysis. Indeed, in the case of malaria vaccination,the RTS,S vaccinees themselves represent a potential goldmine for identifyingthese correlates within a group uniformly exposed to the same immunogensand adjuvant.

This introductory chapter has chronicled the emergence of immunoparasitol-ogy in the latter part of the 20th century, as well its contributions to modernimmunology. Host parasite systems will undoubtedly continue to provide keymodels for the study of immune function and, at the time of writing, theyhave established themselves as major tools for the study of mucosal immuneresponses.

While the goal of global vaccines against parasitic pathogens still eludes us, wecan now, at last, point to tangible progress. It is a tempting, but perhaps notunreasonable, dream that the young scientists entering this field today may, intheir future careers, both directly contribute to and witness the deployment ofimmunisation campaigns against parasitic diseases.

Acknowledgments

I thank Dragana Jankovic, David Sacks, Stephanie James and Tom Nutmanfor helpful discussions. Supported by the Intramural Research Program of theNIAID, NIH.

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