Immune System Investigation Using Parasitic Helminths

Abstract

Coevolutionary adaptation between humans and helminths has developed a finely tuned balance between host immunity and chronic parasitism due to immunoregulation. Given that these reciprocal forces drive selection, experimental models of helminth infection are ideally suited for discovering how host protective immune responses adapt to the unique tissue niches inhabited by these large metazoan parasites. This review highlights the key discoveries in the immunology of helminth infection made over the last decade, from innate lymphoid cells to the emerging importance of neuroimmune connections. A particular emphasis is placed on the emerging areas within helminth immunology where the most growth is possible, including the advent of genetic manipulation of parasites to study immunology and the use of engineered T cells for therapeutic options. Lastly,we cover the status of human challenge trials with helminths as treatment for autoimmune disease, which taken together, stand to keep the study of parasitic worms at the forefront of immunology for years to come.

Keywords: animal models; helminth; innate immunity; lymphocytes; neuroimmunology; transgenesis.

Figure 1

Neuroimmunology of helminth infection. During infection, helminth excretory-secretory products and associated alarmins like IL-33 can stimulate neurons (❶) to release a variety of regulatory factors such as neuromedin U (NMU), vasoactive intestinal peptide (VIP), and calcitonin gene–related peptide (CGRP) (❷). NMU, VIP, and CGRP can activate group 2 innate lymphoid cells (ILC2s) to produce factors such as IL-5, IL-13, amphiregulin (Areg), and serotonin (❸), which are critical for worm clearance and tissue repair (❹). Furthermore, these effector cytokines (❻) can also act on neurons to promote release of more proinflammatory factors like VIP (❼) that help to amplify the type 2 immune response. On the other hand, other neuronal factors like the β2-adrenergic receptor agonist epinephrine, CGRP, and nicotinic acetylcholine receptor agonists can also suppress ILC2s, thereby modulating type 2 inflammatory immune responses (❺). Therefore, the interaction between ILC2s and neurons during helminth infection is mostly bidirectional and can be either proinflammatory or anti-inflammatory. Figure adapted from an image created using Servier Medical Art and licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2

Applications and potential for experimental helminth infection. The principal objective for controlled human infection (CHI) trials with helminth infection is to develop anthelmintic vaccines and drugs as well as helminth therapies for chronic-inflammation-associated disorders (CIADs). The current approach for CHI trials is shown in purple. Typically, samples and data collected from CHI trials include peripheral blood, stool, patient outcomes, and adverse events. These are used to generate data on the safety and efficacy of the vaccine or drug being tested or on the use of helminth infection to treat the CIAD in question. There is significant capacity to increase the potential of CHI trials with helminth infection by performing parallel exploratory studies. Shown in pink, exploratory studies require additional sample collection. Sample sites include the site of inoculation (e.g., sampled by skin biopsy), the site of parasite migration (e.g., sampled by bronchiolar lavage), and the site of infection (e.g., sampled by duodenal biopsies). An unbiased systems approach to generate new hypotheses followed by validation studies will yield additional advancements, including mechanistic understanding of protective immunity and immunomodulation as well as vaccine candidate discovery. This progress toward our principal objectives will inform the rational development of anthelmintic therapeutics and helminth therapies.

Figure 3

Anatomic considerations for targeted transgenesis in parasitic nematodes. Directed transgenesis of parasitic nematodes using tissue-specific promoters would allow for the interrogation of the role of different host immune cells in host-parasite interactions during infestation of tissue-specific niches. Diagram shows regions within gastrointestinal nematodes where tissue-specific promoters exist and the unanswered immunological questions that could be addressed. Abbreviation: ES, excretory-secretory.

Figure 4

Nonmammalian models of helminth immunity. The amenability to genetic manipulation and imaging techniques such as intravital imaging makes Drosophila melanogaster and Danio rerio attractive systems in which to study evolutionarily conserved elements of helminth immunity and discover novel host defense mechanisms. Abbreviations: AMP, antimicrobial peptide; siRNA, small interfering RNA; TALEN, transcription activator–like effector nuclease.