Preface

Helminthiases, caused by the larval or adult stage of various genera of worms, are a serious health and veterinary problem in many developing countries and are considered the most important neglected tropical diseases (NTDs) in developed countries. A great deal of scientific advances have occurred in this field, including in vaccination, epidemiology, drug design, management and diagnostics, and host–parasite interaction at all levels. Recently, the One Health approach has been proposed as a global way to treat and control helminthiasis. This book provides a comprehensive overview of the current state of the art in helminthiases. It highlights the most recent advances in the study of helminth infections, addressing topics such as clinical disease, vaccines, immune response, new possible drug targets, and basic molecular research.

The book is divided into five sections:


Section 1 includes five chapters. Chapter 1, "Therapeutic Properties of *Trichinella spiralis* (Nematoda) in Chronic Degenerative Diseases" by Nevárez-Lechuga et al., discusses diseases produced by helminth parasites. These diseases occur frequently in underdeveloped countries where they present a serious public health problem. However, these regions exhibit a low rate of autoimmune and allergic diseases. As such, some researchers have proposed that some helminths, such as *Trichinella spiralis* or its proteins, have strong anti-inflammatory potential, or have assessed them as modulating agents of the immune response. *T. spiralis* shifts the host immune response from a Th1 profile, characterized by pro-inflammatory cytokines, to a Th2 profile, characterized by the release of different cytokines with anti-inflammatory properties. Thus, the chapter authors point out that this parasite has shown high therapeutic potential in a wide variety of disease models. In one of the most promising, the experimental lupus model in mice, the release of anti-inflammatory cytokines IL-4 and IL-10 and delayed onset of the key clinical features of the experimental lupus model for at least 5 months were observed, when previously parasitized. This is the first study to date that focuses on the use of *T. spiralis* as an

immunomodulator in lupus disease. The authors conclude that further study of the immune response generated by the parasite is necessary to advance the development of new therapies for inflammatory diseases.

Chapter 2, "Anthelmintic Drug Resistance in Livestock: Current Understanding and Future Trends" by Muhammad Abdullah Malik et al., discusses how anthelmintic, ectoparasiticides (insecticides, acaricides) and antiprotozoal chemotherapeutic drugs target parasites. *Chenopodium* oil-like alkaloids, arsenic compounds, cupric sulfate, nicotine, and cupric silicate have been used to destroy nematodes. Unfortunately, these chemicals are less effective and less safe for livestock. The four major groups of broad-spectrum antinematodal compounds are macrocyclic lactones such as milbemycins/ivermectin, benzimidazole/pro-benzimidazole, tetrahydro pyrimidines such as morantel, pyrantel tartrate, and imidazothiazoles such as tetramisole and levamisole. The various factors responsible for gastrointestinal parasitism make it difficult to develop effective control measures. Hence, an effective strategy for the control of parasitic diseases that does not solely rely on anthelmintic therapies needs to be developed at the regional level, based on the epidemiology of the disease.

Chapter 3, "Recent Advances in Anti-Schistosomiasis Drug Discovery" by Ezra J. Marker and Stefan L. Debbert, discusses schistosomiasis, a parasitic disease caused by infection by helminths of the *Schistosoma* genus that affects more than 200 million people, primarily in the developing world. Treatment of this disease largely relies on one drug, praziquantel. Although this drug is cheap, safe, and effective, the looming prospect of drug resistance makes the development of a pipeline of antischistosomiasis drugs a priority. Many new drug leads have arisen from screening existing sets of compounds such as the Open Access Boxes developed by the Medicines for Malaria Venture (MMV) in collaboration with the Drugs for Neglected Diseases Initiative (DNDI). Other leads have been found through work focused on druggable targets such as kinases, histone deacetylases, proteases, and others. Thus, the chapter discusses recent work concerning the discovery and development of novel anti-schistosomiasis drug leads from many sources.

Chapter 4, "Perspective Chapter: Application of Probiotics to Inactivate Helminth Parasitic Zoonosis" by Osama M. Darwesh and Hoda Samir El-Sayed, discusses zoonotic infections, which are animal infections that might be transmissible to people. The infection may be transmitted through ingestion of contaminated food, infected soil, skin penetration, or direct animal contact. Parasitic helminths are a group of parasites that remain poorly studied in comparison to viruses and bacteria but may pose considerable future risk to humans. Zoonotic parasites may be separated into four classes: direct-zoonotic, meta-zoonotic, cyclo-zoonotic, and saprozoonotic. It is possible to prevent helminth parasitic zoonosis via proper hygiene and sanitation or regular deworming with anthelmintic pills. However, because of the lack of effective vaccines and anthelmintic resistance to medication, suppression of parasitic infestation requires new techniques. One potential treatment involves probiotics, which are exogenous residing microorganisms that are beneficial to the host's fitness when administered inside the digestive tract. The most extensively used microorganisms for this purpose are of the genus *Lactobacillus* and *Enterococcus*, along with a few fungi and yeasts.

Chapter 5, "New Uses for Old Drugs and their Application in Helminthology" by Del Río-Araiza et al., examines parasitic infection research performed on both humans and domestic animals. This research has focused mostly on vaccines, diagnostic methods, epidemiology, and the evolutionary origins of parasites, thanks to the emergence of genomics and proteomics. However, the basic biology of the host–parasite interactions of several important medical and veterinary parasites has not been fully studied. Limited information has been obtained on the intricate neuroimmunoendocrine effects of host–parasite interplay. Therefore, the consequences of these interactions, and their possible therapeutic applications, need to be thoroughly investigated. The chapter reviews the available literature on the host–parasite neuroimmunoendocrine network and discusses how this basic research can be used to design new treatments using hormones, anti-hormones, and hormone analogues as a novel therapy against parasitic diseases. In addition, these studies may also contribute to identifying alternative treatments for parasitic diseases in the future. The complex immuneendocrine network may also help in explaining the frequently conflicting results observed in infections with regards to host sex and age and offer helpful insight into other research avenues besides parasite treatment and control strategies. Finally, several natural products isolated from plants, used in traditional medicine, offer an alternative approach for natural products in the preparation of inexpensive and effective antiparasitic drugs.

Section 2 includes four chapters. Chapter 6, "Perspective Chapter: Parasitic Platyhelminthes Nuclear Receptors as Molecular Crossroads" by Adriana Esteves and Gabriela Alvite, discusses research directed at identifying the nuclear receptors (NRs) set expressed by parasitic platyhelminths. Important gaps concerning NRs mechanism of action, ligands, co-regulator proteins, and DNA binding sequences on target genes need to be addressed. Several in vitro effects of host steroid hormones on *Taenia* and *Echinococcus* species have been observed, but the classical mammalian estrogen, androgen, or progesterone receptors couldn't be identified in databases. Nonetheless, novel nuclear receptors and related proteins and genes are being identified and characterized. The elucidation of NRs gene targets as well as ligands in parasitic platyhelminths could allow for the discovery of new and specific pathways differing from those of their hosts. In this sense, these parasitic proteins seem to be good putative targets of new drugs.

Chapter 7, "Perspective Chapter: Molecular Crosstalk and Signal Transduction between Platyhelminths and their Hosts" by Ednilson Hilário Lopes-Junior et al., highlights that parasitic infection is an intimate relationship between host and parasites with an exchange of signal and complex signaling systems involved in these organisms' molecular crosstalk. With the advances of knowledge due to the genomic and transcriptomics projects in the last decades, several genes and the molecular mechanism involved in the biological function of platyhelminths have been described. Cytokines, hormones, and other molecules from the host have influenced the growth, development, and reproduction of platyhelminths. Thus, the authors review the effects of host cytokines (IL-1, IL-4, IL-12, IL-7, TGF-β, TNF-α) and hormones (T4, estrogen, progesterone, and androgens) that directly or indirectly affect parasite development and reproduction and the possible associated signaling pathways.

Chapter 8, "Helminths Derived Immune-Modulatory Molecules: Implications in Host-Parasite Interaction" by Das et al., points out that the parasitic life cycle of helminths greatly relies on sophisticated manipulation of the host environment and successful evasion of the host defense. Helminths produce a repertoire of secretory molecules (extracellular vesicles and/or exosomes) to invade and generate habitable host environments and modulate the host immune responses in such a way that ensures their prolonged survival within the host. The authors present an outline on helminths derived immune-modulatory molecules and their implications in host–parasite crosstalk.

Chapter 9, "Oxygen and Redox Reactions Contribute to the Protection of Free-Living and Parasite Helminths against Pathogens and/or Host Response" by Agustin Plancarte and Gabriela Nava discuss how millions of years ago, the reductive atmosphere environment of Earth was replaced by an oxidative one as a result of oxidation-reduction reactions (redox reactions), which increase the concentration of oxygen. These oxidative conditions allowed aerobic organisms to populate the planet, which acquired mechanisms to both control the toxicity of oxygen and obtain from it via redox reactions energy, both situations, through their aerobic metabolism. In addition, aerobic organisms began to produce reactive oxygen species (ROS) via redox reactions of oxygen molecules. In aerobic organisms, some ROS such as H2O2 function as second messengers in cell signal transduction, allowing for the development of metabolic processes, including gene control. Free-living helminths appeared in the early Paleozoic era and parasite helminths appeared later in the same era. Because of their ancient origins, these organisms represent an excellent research area for biological models. Freeliving helminths, such as *Caenorhabditis elegans* and earthworms, have been used as host models to understand their micro pathogen defenses, particularly those associated with ROS. The chapter discusses the evolution of oxygen molecules and redox reactions, as well as of Earth's atmosphere, and changes over time in the protection mechanisms of helminths.

Section 3 includes three chapters. Chapter 10, "Toxocariasis: From a One Health Perspective" by Fernando Alba-Hurtado and Marco Antonio Muñoz-Guzmán, discusses toxocariasis, which is a neglected zoonotic infection caused by the nematodes *Toxocara canis* and *Toxocara cati*. The distribution of the disease is worldwide and mainly affects dogs and cats. Its larval stage can cause human infection with serious repercussions on the health of its hosts. The infection causes developmental delays, digestive disorders, nonspecific nervous manifestations, and occasionally death associated with hyperparasitosis in some puppies and kittens. In humans, the infection produces clinical syndromes known as visceral larva migrans (VLM), ocular larva migrans (OLM), neurotoxocarosis, and covert toxocariasis. The close contact of people with their pets and the environmental conditions that favor the transmission of this disease place it within the context of one health. The One Health concept is defined as the collaborative efforts of multiple disciplines (medical personnel, veterinarians, researchers, etc.) that work locally, nationally, and globally to achieve optimal health for people, animals, and the environment. From this perspective, toxocariasis is a study model in which classic and recent knowledge of the medical and veterinary area must be combined for its full understanding, with a goal of establishing integrative criteria for its treatment, control, and prevention.

Chapter 11, "*Schistosoma* Hybridizations and Risk of Emerging Zoonosis in Africa: Time to Think of a One Health Approach for Sustainable Schistosomiasis Control and Elimination" by Zacharia et al., discusses the current control of human schistosomiasis in Africa, which is based on preventive chemotherapy and whereby populations are mass-treated with the anthelminthic medication praziquantel. The World Health Organization (WHO) has set a goal of eliminating schistosomiasis as a public health problem and, ultimately, eliminating transmission in all countries where schistosomiasis is endemic by 2030. However, recurrent hybridization between *Schistosoma* species is an emerging public health concern that has a major impact on distribution of the disease and ultimately may derail elimination efforts. The One Health approach recognizes interconnections between the health of humans, animals, and the environment, and encourages collaborative efforts toward the best outcomes. Thus, this chapter explains how the One Health approach can accelerate the control and elimination of schistosomiasis in Africa.

Chapter 12, "Dancing in a Cycle: Global Health Agenda and *Schistosomiasis* Control in Africa" by Adetayo Olorunlana, discusses that schistosomiasis and other NTDs affect about 2 billion people globally. Africa shares approximately 90% of the global burden of schistosomiasis disease. Despite, WHO efforts to control the disease, it remains neglected in most African countries. Control programs exclude adults in Mass Drug Administration (MDAs), and water, sanitation, and hygiene (WASH) because the drug praziquantel is used for treatment. However, migratory patterns of the neglected population and the interplay of social, economic, political, and cultural factors have introduced the disease into previously eliminated and/or new areas. The question is whether Africa can achieve the new goals of the WHO NTDs 2021–2030 Roadmap for schistosomiasis elimination. The chapter compares and contrasts Africa's current topdown approach to schistosomiasis control to a dynamic approach. Or if the previous pattern of late implementation, dependent on only one drug and shifting focus to other diseases of relevance continues. If a new approach is not adopted the dance in the cycle has just begun.

Section 4 includes five chapters. Chapter 13, "Perspective Chapter: Integrated Root-Knot Nematodes (*Meloidogyne*) Management Approaches" by Ahmad et al., describes the *Meloidogyne* genus, which contains the most prevalent and harmful worms formally known as root-knot nematode species. They attack a wide range of plants belonging to different plant families. In the infective second stage, juveniles (J-II) feed on the plant's roots and, as a result, the host plant roots become swollen/produce galls. The attack plant shows stunted growth and in extreme cases the plant dies. An integrated pest management (IPM) approach is required to tackle these harmful nematodes spp. The integrated tactics include cultural/agronomic practices as well as biological and chemical control. A sole management method is not enough to deal with the root-knot nematode. Therefore, a proper IPM package is required for the farmer to gain good health for the crops.

Chapter 14, "Perspective Chapter: The Potential Role of Nematode Parasites in Wildlife Decline – Evidence from Allegheny Woodrats (*Neotoma magister*), Northern Flying Squirrels (*Glaucomys sabrinus*) and now the Eurasian Red Squirrel (*Sciurus vulgaris*)" by Carolyn Mahan and Michael Steele points out that global climate change and human-induced habitat loss alter the landscape for

native wildlife, resulting in shifts in geographic ranges, occupation of smaller, remnant habitat patches, or use of novel environments. These processes often lead to sympatry between species that historically occupied non-overlapping ranges and habitats. Such interactions may result in increased competition for resources and expose species to novel parasites that adversely affect a species' fitness, leading to wildlife declines. The chapter explores these interactions in two species of endangered North American rodents: Northern flying squirrels (*Glaucomys sabrinus*) and Allegheny woodrats (*Neotoma magister*). Northern flying squirrels are declining in the eastern United States due to competition with its congener, southern flying squirrels (*Glaucomys volans*). Increasing evidence indicates that this competition is mediated by a shared intestinal nematode, *Strongyloides robustus*. Transmission of this nematode to the endangered northern flying squirrel may be increasing due to habitat loss, forest fragmentation, and climate change. Climate change causes the northward range expansion of southern flying squirrels and adversely affects the health of coniferous forests, which is the preferred habitat of northern flying squirrels. The chapter authors also note the most recent discovery of *S. robustus* as a factor in the decline of the European red squirrel (*Sciurus vulgaris*). *S. robustus* is a novel parasite to this host in Europe and was introduced along with the invasive eastern gray squirrel (*Sciurus carolinensis*) that is native to North America. Likewise, in Allegheny woodrats, shrinking habitat and landscape changes have resulted in increased range overlap with raccoons (*Procyon lotor*), which harbor a nematode fatal to woodrats. The chapter also discusses the subsequent transmission of this nematode, *Baylisascaris procyonis*, to woodrats as a contributing factor to their decline throughout the Appalachian Mountains.

Chapter 15, "Soil-Transmissible Helminths Infections; Diagnosis, Transmission Dynamics, and Disease Management Strategies in Low-and Middle-Income Countries" by James-Paul Kretchy, examines soil-transmissible helminthes (STHs) infections, which are among the most common sanitation-related public health problems among people living in poor settlements of tropical and subtropical regions in low- and middle-income countries (LMICs). Though available data suggest occurrence of disease in adults, children of school-going age bear the greatest burden, as these infections affect their cognitive development and physical growth. The characteristic high levels of poverty, poor environmental hygiene, open defecation practices, and inadequate sanitation and waste management systems expose residents to the risks of STH infections. Walking bare-footed, inappropriate hand hygiene behavior, and the unavailability/ improper use of personal protective equipment (PPE) can impact transmission risks in endemic communities and among occupational risk groups. These must be properly investigated and managed, and appropriate interventions must be communicated to decision-makers.

Chapter 16, "Zoonotic Trematode Infections; Their Biology, Intermediate Hosts and Control" by Henry Madsen and Jay R. Stauffer, Jr., point out that many diseases linked with trematodes are zoonotic, including liver flukes (*Fasciola spp*., *Clonorchis*, and *Opistorchis* are the most common), intestinal flukes (some species of *Heterophyidae*), lung flukes (*Paragonimus* spp.), and the blood flukes (*Schistosome* species). A characteristic of all these species is that they have a vertebrate as the final host and

freshwater snail species as the first intermediate host. The foodborne trematodes also have a second intermediate host where their infective stage (metacercariae) lodge or in case of the Fasciolidae, cercariae encyst on aquatic or semi-aquatic plants. The chapter describes the biology of transmission with emphasis on the intermediate snail hosts and their control.

Chapter 17, "Biology of the Human Filariases" by Jesuthas Ajendra, Achim Hoerauf, and Marc P. Hübner discusses filarial nematodes, which are parasitic worms transmitted by blood-feeding insects. They cause some of the most debilitating infectious diseases known to humankind. Mainly found in tropical and subtropical areas of the developing world, diseases such as lymphatic filariasis and onchocerciasis represent major public health issues. With millions of people infected and billions at risk of infection, these diseases can stun economic growth and impair quality of life of the affected regions. As such, the WHO has classified both lymphatic filariasis and onchocerciasis as NTDs. The lesser-known filarial disease loiasis not only affects millions of people, but also represents a huge obstacle during mass drug administration programs targeting other filarial diseases. Even less is known about mansonellosis, potentially the most widespread of the human filariases but underestimated due to the lack of clinical symptoms. Large-scale intervention as well as mass drug administration programs are undertaken with the long-term goal of eliminating filarial diseases, as declared in the WHO roadmap 2021–2030. However, there is still neither a vaccination nor short-term macrofilaricidal treatments available. Many drugs have side effects or are not suitable for all patients and thus there are still billions of people living in areas with a high risk of infection.

Section 5 includes two chapters. Chapter 18, "Perspective Chapter: Advances in the Development of Anti-*Trichinella spiralis* Vaccine, Challenges, and Future Prospective" by Aleem et al., discusses trichinellosis, which is a very important foodborne zoonosis caused by *Trichinella spiralis*. This is an important disease and its causative agent is prevalent throughout the world (cosmopolitan). More clinical awareness of trichinellosis is required due to its many outbreaks and the increase in the consumption of pork meat and its byproducts. Trichinellosis is epizootic in nature and its economic burden is associated with the prevention of this disease from the human food chain. This disease is transmitted from animals to humans through the consumption of raw or undercooked meat containing encapsulated muscle larvae of *T. spiralis*. This chapter demonstrates the direct effect of progesterone (P4) and mifepristone (RU486) on the progesterone receptors of *T. spiralis*. It also examines the challenges in the preparation of DNA and recombinant protein vaccination to control trichinellosis.

Finally, Chapter 19, "Perspective Chapter: Multi-Omic Approaches to Vaccine Development against Helminth Diseases" by Daga et al., discusses the need for protective vaccines for humans and livestock against helminth diseases. The "-omics" era has led to renewed interest in vaccine development against helminth diseases, as candidate vaccines can now be designed, evaluated, and refined in a fraction of the time previously required. In this chapter, the authors describe and review genomic, transcriptomic, and proteomic approaches to the design of vaccines against helminth diseases.

We hope that readers find this book helpful and informative. It is our attempt to compile novel and important information about diseases and parasites that are a health burden in underdeveloped countries and an emerging health problem in developed ones.

#### **Jorge Morales-Montor**

Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
