Ascaris

The Neglected Parasite

Celia Holland

• Publisher: Academic Press
• Year: 2013
• Print ISBN: 9780123969781
• eBook ISBN: 9780123972859
• Topic: Medicine
• Subtopic: Immunology

This book tackles a number of different perspectives concerning the parasitic helminth Ascaris, both in animals and in humans and the disease known as ascariasis. It seeks to identify interesting, exciting and novel aspects, which will interest readers from a broad range of disciplines.Over a quarter of the world's population are infected with the human roundworm, and the equivalent in pigs is equally ubiquitous. Both contribute to insidious and chronic nutritional morbidity, and this has been quantified, in humans, as disability adjusted life years approximating 10.5 million. Ascaris larvae develop in host parenteral tissues, and the resultant pathology has been condemnation. Ascariasis, despite its staggering global prevalence and the sheer numbers of people it infects, remains a classic neglected disease. However, renewed interest in the consequences of early infection with worms from the perspective of immune modulation, co-infections and the development of allergy further enhances the relevance of these parasites.- Brings together a wide range of topics and approaches and recent, comprehensive and progressive research concerning the neglected parasite Ascaris- Provides a blueprint of how a single parasite entity can stimulate interest in basic biology, clinical science, veterinary science, public health and epidemiology- Presents a wealth of new insights given that a book on this parasite has not been published for over 20 years- 16 chapters from a range of top authors from around the world

Part I

Biology of Ascaris

Chapter 1 Immunology of Ascaris and Immunomodulation

Chapter 2 Ascaris and Allergy

Chapter 3 Ascaris – Antigens, Allergens, Immunogenetics, Protein Structures

Chapter 4 Implications of Ascaris Co-infection

Chapter 1

Immunology of Ascaris and Immunomodulation

Professor Philip J. Cooper^∗ and Professor Camila A. Figuieredo^†, ^∗Liverpool School of Tropical Medicine and Hygiene, Liverpool, UK; Pontificia Universidad Católica del Ecuador, Quito, Ecuador, ^†Universidade Federal da Bahia, Salvador, Brazil

Outline

Introduction

Immunology of Ascariasis

Immunology of Ascaris suum in Pigs

Immunology of Ascariasis in Humans

Immune Modulation in Animal Models

Evidence for Clinically Relevant Immune Modulation by Ascariasis During Natural Infection

Vaccine Immune Responses

Atopy

Asthma

Conclusion

References

Introduction

The large roundworms, Ascaris lumbricoides and A. suum, are ubiquitous pathogens of humans and pigs respectively with worldwide distributions. A. suum and A. lumbricoides are highly related genetically and are able to cross-infect pigs and humans. Although it has been suggested that they represent the same species,¹ this remains an area of controversy² (see Chapter 10).

Both A. suum in pigs and A. lumbricoides in humans have similar life-cycles in which the mammalian host is infected orally with infective ova. Larvae hatch in the small intestine and migrate to the caecum and proximal colon where they penetrate the mucosa,³ and migrate to the liver through the portal system. The larvae reach the lungs via the systemic circulation where they embolize in the pulmonary capillaries, penetrate the alveoli, and are coughed up and then swallowed reaching the small intestine about 2 weeks following infection.⁴ Roundworms reach sexual maturity in the small intestine where female and male adults mate. Fecund females release hundreds of thousands of eggs daily into the host feces.

In pigs, the majority of A. suum larvae are expelled between 2 and 3 weeks after infection⁵ and among those that survive and develop into adults, most are expelled from the pig intestine within 6 months.⁶ In the case of A. lumbricoides in humans there are no published data to our knowledge on the survival of larvae and adults although adult A. lumbricoides may survive 1 to 2 years in the human gut.⁷

Host susceptibility and genetics play an important role in the distribution of parasites within human and pig populations characterized by an aggregated distribution of parasites in which few individuals harbor the majority of parasites while most have few or no parasites^6,8 (see Chapter 7). Resistance to infection and the acquisition of resistance upon exposure are determined largely by the host innate and adaptive immune response. Recent research, particularly of A. suum in the pig, has identified specific immune parameters associated with the development of protective immunity that may be relevant also to our understanding of immunity to A. lumbricoides in humans. The long-term survival of parasites in the host depends on the modulation of the host’s immune response by the parasite. Understanding the mechanisms by which chronic infections modulate the immune response will allow us to understand better immune modulation and homeostasis in mucosal and other tissues.^9,10 It has been suggested that the relative absence of chronic parasitic infections such as A. lumbricoides and their immune modulatory effects may have a role in the emerging epidemic of inflammatory diseases such as autoimmune and allergic diseases in populations living in industrialized countries^11–14 and also urbanizing populations in non-industrialized countries.

This chapter will review what is known of the immune response to Ascaris in pigs and humans and how infections may modify the immune and inflammatory response of the host. We will also discuss the potential clinical effects of this immune modulation.

Immunology of Ascariasis

Immunology of Ascaris suum in Pigs

Great progress has been made over the past 20 years in our understanding of the immune response to A. suum in pigs. Earlier studies showed that the inoculation of pigs with infective eggs was associated with the development of specific systemic IgG1, IgA, and IgM antibody responses,^5,15 but that the predominant antibody secreting cells (ASC) in the mucosa of the proximal jejunum,⁵ duodenum,¹⁶ and bronchi¹⁶ were of the IgA isotype.⁵ That the immune response to A. suum in the pig is predominantly Th2 is reflected by an elevated peripheral blood eosinophilia,^17,18 elevated frequencies of parasite-specific monocytes secreting IL-4 in peripheral blood and intestinal lymph nodes,¹⁸ and the increased expression of IL-4 in plasma and Th2 cytokines (e.g. IL-4 and IL-13) in the intestine^19,20 and liver.²¹ An increased expression of IL-10 has been observed in the intestine and other tissues during infection¹⁹ where it may have a role in the regulation of inflammation.²²

Resistance to A. suum in pigs has been observed following multiple oral infections with A. suum eggs,^17,23,24 with radiation-attenuated A. suum eggs,^25,26 and following immunization with parasite-derived products.²⁷ Partial protection has also been achieved by giving colostrum from immunized sows²⁸ and by passive transfer of hyperimmune sera.²⁸ Protective immunity to A. suum in swine may occur in the liver, lungs, and in the intestine. Different infection or immunization strategies may have stronger effects on immunity generated in a particular tissue. A strong liver white-spot reaction, reflecting the host inflammatory response to the presence of the larvae in the liver, is a typical consequence of a secondary challenge exposure to infective eggs,²⁹ although this reaction diminishes over time with trickle infections.²⁴

Chronic natural and multiple inoculations with eggs has been associated with the development of pre-hepatic intestinal immunity^29,30 while immunization with irradiated eggs or with A. suum antigens^27,31 is associated with post-hepatic protective immunity. Relatively little is known of the specific immunological mechanisms by which protection is achieved. The intestinal expulsion of larvae that have migrated through the lungs has been associated with an increase in the frequency of intestinal mucosal ASCs producing parasite-specific IgA⁵ and with mast cell-mediated immediate hypersensitivity responses to parasite antigens.^4,32 Non-specific immunological mechanisms may also have a role: pigs previously infected with transmissible gastroenteritis (TGE) virus were resistant to infection.³³ Intestinal immunity to A. suum eggs does not appear to be directly related to the number of adult worms in the host because removal of adults by anthelmintic treatment or the direct transplantation into the intestine did not affect protective immunity following challenge with A. suum eggs.¹⁷

Immunology of Ascariasis in Humans

Chronic infections with A. lumbricoides in humans are associated with the production of high levels of specific and non-specific antibodies of all isotypes and IgG subclasses^34,35 and a cytokine response characterized by the production of Th2 cytokines (i.e. IL-4, IL-13, and IL-5) by peripheral blood monocytes (PBMCs) and leukocytes (PBLs in whole blood cultures).^36–38 Other Th2 effector responses are also prominent during infection, reflected by elevated numbers of peripheral blood eosinophils³⁹ and increased expression of eosinophil degranulation products.¹⁰ The production of IFN-γ by PBMCs/PBLs stimulated with Ascaris antigens is not prominent in ascariasis^37,38,40,41 but IL-10 production may be increased in infected individuals.^37,42 An increased production of IL-10 has been observed also to occur spontaneously (i.e. in the absence of antigen stimulation) by PBMCs/PBLs of individuals with chronic infections,^10,38 an observation previously made for other chronic helminth infections.^43–45 Albendazole treatment of individuals co-infected with HIV and A. lumbricoides was associated with a decline in plasma IL-10 compared to co-infected individuals receiving placebo,⁴⁶ providing further evidence that IL-10 may be upregulated non-specifically in infected individuals.

IL-10 is considered to be a key cytokine mediating immune regulation during chronic helminth infections^{10,38,43–45,47} and the combination of elevated Th2 cytokines with IL-10 has been referred to as a modified or regulated Th2 response.^48,49 Another cytokine that has been associated with immune regulation during chronic helminth infections is TGF-β⁴³: evidence for the increased expression of this cytokine during ascariasis is inconsistent with some studies suggesting increased production or expression of TGF-β1^34,47 but other authors have observed no such effect.^10,41 It should be remembered that individuals living in endemic areas are often infected with more than one soil-transmitted helminth (STH) parasite and many children with A. lumbricoides, particularly those with high parasite burdens, have a high probability of recent or current STH co-infections (see Chapter 4). This makes it more difficult to attribute specific immunologic effects to ascariasis alone even when blood cells are stimulated in vitro with Ascaris antigens because of the high degree of immunological cross-reactivity between STH antigens.⁵⁰

The existence of protective immunity to ascariasis in humans remains controversial but is suggested by the observation that, under conditions of high levels of transmission, the prevalence and intensity of A. lumbricoides declines with age.⁵¹ Non-immunological factors, such as changes in behavior with age, are reasonable alternative explanations for this observation. Even so, a number of investigators have tried to identify immunological parameters associated with protection.

A study of reinfection following treatment was unable to attribute a protective role of specific antibodies to adult and larval stages of A. lumbricoides against current infection or reinfection,³⁵ while other studies have suggested that specific IgE might have a protective role.^52,53 A randomized clinical trial giving anti-IgE for the treatment for atopic diseases, which reduced circulating levels of IgE to negligible levels, did not show a signific...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Foreword
• Contributors
• Introduction
• Part I: Biology of Ascaris
• Part II: Model Systems
• Part III: Epidemiology of Ascariasis
• Part IV: Host and Parasite Genetics
• Part V: Clinical Aspects and Public Health
• Index