Of Dogs and Hookworms: Man’S Best Friend and His Parasites As a Model for Translational Biomedical Research Catherine Shepherd*, Phurpa Wangchuk and Alex Loukas*
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Shepherd et al. Parasites & Vectors (2018) 11:59 DOI 10.1186/s13071-018-2621-2 REVIEW Open Access Of dogs and hookworms: man’s best friend and his parasites as a model for translational biomedical research Catherine Shepherd*, Phurpa Wangchuk and Alex Loukas* Abstract: We present evidence that the dog hookworm (Ancylostoma caninum) is underutilised in the study of host-parasite interactions, particularly as a proxy for the human-hookworm relationship. The inability to passage hookworms through all life stages in vitro means that adult stage hookworms have to be harvested from the gut of their definitive hosts for ex vivo research. This makes study of the human-hookworm interface difficult for technical and ethical reasons. The historical association of humans, dogs and hookworms presents a unique triad of positive evolutionary pressure to drive the A. caninum-canine interaction to reflect that of the human-hookworm relationship. Here we discuss A. caninum as a proxy for human hookworm infection and situate this hookworm model within the current research agenda, including the various ‘omics’ applications and the search for next generation biologics to treat a plethora of human diseases. Historically, the dog hookworm has been well described on a physiological and biochemical level, with an increasing understanding of its role as a human zoonosis. With its similarity to human hookworm, the recent publications of hookworm genomes and other omics databases, as well as the ready availability of these parasites for ex vivo culture, the dog hookworm presents itself as a valuable tool for discovery and translational research. Keywords: Ancylostoma caninum, Human hookworm, Hookworm model, Translational model, Omics Background of the 1950s that widespread elimination of STH was “His name is not Wild Dog any more, but the First Friend, attempted [7–10]. because he will be our friend for always and always and As we approached the 21st century, rather than cele- always.” Rudyard Kipling brating the worldwide demise of STH, drug failures and Over one-third of people on the planet harbour a incomplete coverage has meant the persistence of this parasitic helminth [1, 2]. Helminth infections are foe. Previously, effective drugs like mebendazole and responsible for a host of morbidities that trap people in other benzimidazole anthelmintics are now unable to a cycle of poverty. Moreover, parasitic diseases kill completely eliminate STH infections [1, 11–18]. Histor- millions of people each year, primarily in developing ical evidence suggests that drugs alone will not result in countries of the tropics [3, 4]. Over 80 percent of the elimination of STH infection and the development helminth infections are caused by soil transmitted hel- of resistance to benzimidazoles in gastrointestinal nema- minths (STH) [5]. Elimination of STH in Western soci- todes of livestock [19–21] is a major point of concern ety started in the early 20th century as a result of better for human STH infections, due to the reliance on alben- sanitation and public sewerage programs [6]. The prob- dazole for human hookworm treatment. Indications are lem of helminth infections in developing nations was that other means of control should be at the fore of recognised, but it was not until the advent of anthelmin- research and development agendas [3, 22–24]. Two such tic drugs and the World Health Organisation initiatives avenues are the identification of new anthelmintic com- pounds [25, 26] and the development of vaccines that * Correspondence: [email protected]; are effective against STH [3, 27]. Key to this research is [email protected] a fundamental understanding of the interactions Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, between helminths and their environments as well as Cairns, Australia the key signals that helminths require from their hosts © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shepherd et al. Parasites & Vectors (2018) 11:59 Page 2 of 16 to facilitate their extraordinary parasitic existence [10]. dogs a natural animal model for human disease [48]. Characterising parasitic helminths at a deep molecular Figure 1 illustrates the triad relationship of hookworms, level will reveal vulnerable pathways that can be humans and canines. Sharing environments with each exploited by novel drugs [10, 28], and molecules of im- other increases the risk of cross-infection with each mutable vaccine antigen potential [29, 30]. other’s parasites. We know that Strongyloides, Toxocara, Developing nations are not the only benefactors of tapeworms and hookworms can be passed from dogs to hookworm research. Indeed, in developed countries humans and bidirectional transfer occurs in some cases, there is an increase in the incidence of autoimmune and acting as pools for reinfection. allergic diseases that has been linked to lack of exposure to pathogens such as STH [31]. It is apparent from epi- Dogs as functional models for human disease demiological studies [32–36] and clinical trials [37, 38] The parallel evolution between dog and human may that the immunomodulatory inputs provided by expos- have driven the predisposition to autoimmune diseases ure to STH and other pathogens assist in the develop- through antagonistic pleiotropy [41]. Diseases that have ment and maintenance of a healthy immune system in underlying similarities to human disease can be utilised humans. Characterising helminth-driven immunoregula- for the study of aetiology and treatment. Genetic bottle- tion at a molecular level will shed light on the aetiology necks that have occurred in dog breed conformation of inflammatory diseases, and may uncover important have meant that many dog breeds are good models for disease/pathology pathways that can be targeted by both monogenic and complex genetic human diseases helminth-derived therapeutics [39, 40]. [48]. For example: The identification of a suitable model for the study of such a broad research agenda examining both the bene- Nova Scotia duck tolling retrievers develop canine fits of iatrogenic helminth infections and the pathogen- systemic lupus erythematosus which is homologous esis of STH infections needs to be carefully considered. to human systemic lupus erythematous (SLE) [48] The benefit is the generation of a large amount of trans- Osteogenesis imperfecta (brittle bone disease) in latable research data coupled with an economy of scien- beagles and golden retrievers (polygenic disease) [49, tific effort and resources. Fruitful models ideally need to 50] be naturally occurring (i.e. not a human parasite manip- A number of dog breeds (Pembroke Welsh corgi, ulated to survive in experimental animals) and closely Boxer, Rhodesian ridgeback, German Shepherd dog, resemble the relationship between a STH and its human and Chesapeake Bay retriever) develop canine host. The human-hookworm-dog axis reflects an intim- degenerative myelopathy, an amyotrophic lateral ate evolutionary relationship between three organisms, a sclerosis-like disease that has similar underlying gen- triad that presents a naturally selected model for inte- etic basis in humans (sod1 gene) [51] grated research. The dog hookworm, primarily Ancylos- Diseases such as narcolepsy [52], cancers [53, 54] toma caninum, is discussed in this context in this and obsessive-compulsive disorder [55] that occur in review. humans have the same underlying genetic basis in dogs Of humans, hookworms and hounds: the relationship between humans, hookworms and dogs is enduring and Diseases like diabetes that occur in both humans and nuanced dogs and are polygenic with similar underlying single For thousands of years (estimated to be anywhere be- nucleotide polymorphisms (SNPs) in T helper 2 type cy- tween 14,000 and ~35,000 years [41]) humans and ca- tokines, reflect the complex environmental and genetic nines have shared the same evolutionary drivers. The sequelae in the development of this disease [56]. Simi- process of domestication has resulted in positive select- larly, dilated cardiomyopathy (DCM) is associated with a ive pressure on dogs to be more like humans for thou- large number of homologous genes in both humans and sands of generations [42–44]. Genetic evidence suggests canine breeds [57], making these dogs excellent models that dogs were domesticated from wolves [45], with suc- for the study of this disease in humans. These parallels cessive domestication events occurring over at least between human and dog diseases mean that canine 33,000 years [41]. Importantly, dogs accompanied models provide identification, diagnostic and therapeutic humans over the threshold from hunter gatherers to research opportunities in a naturally occurring animal agricultural based societies, and this close association model. with humans has meant that dogs have evolved to toler- The case of dogs and inflammatory bowel disease ate diets rich in