The role of evolutionary biology in research and control of liver flukes in Southeast Asia

Abstract

Stimulated largely by the availability of new technology, biomedical research at the molecular-level and chemical-based control approaches arguably dominate the field of infectious diseases. Along with this, the proximate view of disease etiology predominates to the exclusion of the ultimate, evolutionary biology-based, causation perspective. Yet, historically and up to today, research in evolutionary biology has provided much of the foundation for understanding the mechanisms underlying disease transmission dynamics, virulence, and the design of effective integrated control strategies. Here we review the state of knowledge regarding the biology of Asian liver Fluke-host relationship, parasitology, phylodynamics, drug-based interventions and liver Fluke-related cancer etiology from an evolutionary biology perspective. We consider how evolutionary principles, mechanisms and research methods could help refine our understanding of clinical disease associated with infection by Liver Flukes as well as their transmission dynamics. We identify a series of questions for an evolutionary biology research agenda for the liver Fluke that should contribute to an increased understanding of liver Fluke-associated diseases. Finally, we describe an integrative evolutionary medicine approach to liver Fluke prevention and control highlighting the need to better contextualize interventions within a broader human health and sustainable development framework.

Keywords: Epidemiology; Evolution; Host-parasite; Infectious disease; Opisthorchis; Transmission.

Fig. 1. O. viverrini transmission cycle

Human infection occurs when cyprinid fish bearing metacercariae in their tissues and organs are consumed raw or partially cooked (including smoked, pickled and salted ; Grundy-Warr et al., 2012). Metacercariae in the fish excyst in the duodenum and enter the bile ducts, where they mature sexually. The adult worms produce eggs which are passed out in faeces to the environment. When freshwater Bithynia snails ingest the eggs, miracidium hatch and develop into sporocysts which undergo asexual multiplication, and develop into rediae and cercariae. Upon release in the environment, free-swimming cercariae actively search for a fish host, most often from the cyprinidae family, to penetrate the tissues and skin and develop into metacercariae infective to humans and other fish-eating mammals (Kaewkes, 2003; Wykoff et al., 1965).

Fig. 2. A dynamic view of O. viverrini infection and associated clinical risks

A) Liver fuke infection may vary from beneficial to costly depending on the infection intensity which for sake of simplicity in the figure we categorize as Low (L), Moderate (M) or High (H). The infection intensity will influence the relative dominance of anti-inflammatory and beneficial TH2 responses vs pro-infammatory harmful/costly TH1 responses. In case of chronic immuno-modulation by the Fluke and associated reduction of inflammation, the benefits can be a reduced risk of autoimmune and allergic diseases as well as metabolic disorders including obesity, cardiovascular and type 2 diabetes (in the figure lowest panel (L) the benefits (+) outweight the costs (−)). In case of chronic inflammation when Th1 response dominates and impart costs to the host (i.e. in the upper panel of the figure, costs (−) are higher than benefits (+)). Costs of infection range from anemia, hepathobiliary abnormalities to more severe pathologies such as fibrosis, cholangitis, hepatoegaly and in combination with other risk factors such as alcohol, Cholangiocarcinoma. The thresholds (the line represented in the middle of the figure) - beyond which infection intensity triggered hyper-inflammation and where the costs outwheight the benefits - are dynamic and change in relation to the host genetic background, diet and lifestyle as well as microbiome. B) Health assessments incoprorating knowledge about infection intensity, genetic predisposition to inflammation as well as lifestyle is necessary to refine interventions and avoid disrupting possible beneficial settings. When costs of infection are found to outwheight potential benefits, intervention, likely drug administration (chemotherapy) is warranted. When the benefits are thought to outwheight the costs (in case of low intensity infection) intervention and drug administration may be nuanced as possibly administrering drug in this case can lead to unwanted clinical conditions that are more detrimental than having a low worm burden. This « trade-off » rationale should help design epidemiological investigation where risk groups (risk of developping severe hepathobiliary conditions) are defined based on infection intensity and if possible other biological and socio-economic attributes as advocated by the WHO (Montresor et al. 1998).

Fig. 3. The evolutionary consequences of hosts migrations for Complex Life Cycle parasites (CLP) local adaptations

Migration rates often vary among the different hosts of a CLP. The migration rate of a CLP is expected to be most similar to that of its most mobile host—in this case the definitive host. Immigration of mobile hosts into a population can supply novel parasite genotypes, promoting parasite LA to the less-mobile host (which experience movement restriction at smaller scales. In snail populations, finer grain movement restriction may foster tighter genetic local adaptations as one snail subpopulation is likely to be exposed to a unique Ov local strain (in the figure, eggs from one particular color only encounter snails from one particular color). Fish are likely to be exposed to several Ov strains as they can navigate entire wetlands or watersheds (fish from one colour can encounter a limited number of cercariae of different colors). Human hosts are sharing fish and parasite from different wetlands, watersheds and even regions which contributes to parasite genotype mixing and fosters exposure to a greater diversity of parasite lineages hence minimizing tight local co-adaptations. *AH = Alternate Hosts.