Opportunities and challenges for modelling epidemiological and evolutionary dynamics in a multihost, multiparasite system: Zoonotic hybrid schistosomiasis in West Africa

Multihost multiparasite systems are evolutionarily and ecologically dynamic, which presents substantial trans‐disciplinary challenges for elucidating their epidemiology and designing appropriate control. Evidence for hybridizations and introgressions between parasite species is gathering, in part in line with improvements in molecular diagnostics and genome sequencing. One major system where this is becoming apparent is within the Genus Schistosoma, where schistosomiasis represents a disease of considerable medical and veterinary importance, the greatest burden of which occurs in sub‐Saharan Africa. Interspecific hybridizations and introgressions bring an increased level of complexity over and above that already inherent within multihost, multiparasite systems, also representing an additional source of genetic variation that can drive evolution. This has the potential for profound implications for the control of parasitic diseases, including, but not exclusive to, widening host range, increased transmission potential and altered responses to drug therapy. Here, we present the challenging case example of haematobium group Schistosoma spp. hybrids in West Africa, a system involving multiple interacting parasites and multiple definitive hosts, in a region where zoonotic reservoirs of schistosomiasis were not previously considered to be of importance. We consider how existing mathematical model frameworks for schistosome transmission could be expanded and adapted to zoonotic hybrid systems, exploring how such model frameworks can utilize molecular and epidemiological data, as well as the complexities and challenges this presents. We also highlight the opportunities and value such mathematical models could bring to this and a range of similar multihost, multi and cross‐hybridizing parasites systems in our changing world

Modelling environmentally-mediated infectious diseases of humans: transmission dynamics of schistosomiasis in China.

Macroparasites of humans are sensitive to a variety of environmental variables, including temperature, rainfall and hydrology, yet current comprehension of these relationships is limited. Given the incomplete mechanistic understanding of environment-disease interactions, mathematical models that describe them have seldom included the effects of time-varying environmental processes on transmission dynamics and where they have been included, simple generic, periodic functions are usually used. Few examples exist where seasonal forcing functions describe the actual processes underlying the environmental drivers of disease dynamics. Transmission of human schistosomes, which involves multiple environmental stages, offers a model for applying our understanding of the environmental determinants of the viability, longevity, infectivity and mobility of these stages to controlling disease in diverse environments. Here, a mathematical model of schistosomiasis transmission is presented which incorporates the effects of environmental variables on transmission. Model dynamics are explored and several key extensions to the model are proposed

Schistosomes and snails: A molecular encounter

Copyright © 2014 Knight, Arican-Goktas, Ittiprasert, Odoemelam, Miller and Bridger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Copyright © 2014 Knight, Arican-Goktas, Ittiprasert, Odoemelam, Miller and Bridger. Biomphalaria glabrata snails play an integral role in the transmission of Schistosoma mansoni, the causative agent for human schistosomiasis in the Western hemisphere. For the past two decades, tremendous advances have been made in research aimed at elucidating the molecular basis of the snail/parasite interaction. The growing concern that there is no vaccine to prevent schistosomiasis and only one effective drug in existence provides the impetus to develop new control strategies based on eliminating schistosomes at the snail-stage of the life cycle. To elucidate why a given snail is not always compatible to each and every schistosome it encounters, B. glabrata that are either resistant or susceptible to a given strain of S. mansoni have been employed to track molecular mechanisms governing the snail/schistosome relationship. With such snails, genetic markers for resistance and susceptibility were identified. Additionally, differential gene expression studies have led to the identification of genes that underlie these phenotypes. Lately, the role of schistosomes in mediating non-random relocation of gene loci has been identified for the first time, making B. glabrata a model organism where chromatin regulation by changes in nuclear architecture, known as spatial epigenetics, orchestrated by a major human parasite can now be investigated. This review will highlight the progress that has been made in using molecular approaches to describe snail/schistosome compatibility issues. Uncovering the signaling networks triggered by schistosomes that provide the impulse to turn genes on and off in the snail host, thereby controlling the outcome of infection, could also yield new insights into anti-parasite mechanism(s) that operate in the human host as well.NIH-NIAID and the Malacological Society of London

Measuring fitness of Kenyan children with polyparasitic infections using the 20-meter shuttle run test as a morbidity metric.

BACKGROUND: To date, there has been no standardized approach to the assessment of aerobic fitness among children who harbor parasites. In quantifying the disability associated with individual or multiple chronic infections, accurate measures of physical fitness are important metrics. This is because exercise intolerance, as seen with anemia and many other chronic disorders, reflects the body's inability to maintain adequate oxygen supply (VO(2) max) to the motor tissues, which is frequently linked to reduced quality-of-life in terms of physical and job performance. The objective of our study was to examine the associations between polyparasitism, anemia, and reduced fitness in a high risk Kenyan population using novel implementation of the 20-meter shuttle run test (20mSRT), a well-standardized, low-technology physical fitness test. METHODOLOGY/PRINCIPAL FINDINGS: Four villages in coastal Kenya were surveyed during 2009-2010. Children 5-18 years were tested for infection with Schistosoma haematobium (Sh), malaria, filaria, and geohelminth infections by standard methods. After anthropometric and hemoglobin testing, fitness was assessed with the 20 mSRT. The 20 mSRT proved easy to perform, requiring only minimal staff training. Parasitology revealed high prevalence of single and multiple parasitic infections in all villages, with Sh being the most common (25-62%). Anemia prevalence was 45-58%. Using multiply-adjusted linear modeling that accounted for household clustering, decreased aerobic capacity was significantly associated with anemia, stunting, and wasting, with some gender differences. CONCLUSIONS/SIGNIFICANCE: The 20 mSRT, which has excellent correlation with VO(2), is a highly feasible fitness test for low-resource settings. Our results indicate impaired fitness is common in areas endemic for parasites, where, at least in part, low fitness scores are likely to result from anemia and stunting associated with chronic infection. The 20 mSRT should be used as a common metric to quantify physical fitness and compare sub-clinical disability across many different disorders and community settings

The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni

Natural selection acts on all organisms, including parasites, to maximise reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian State-Space Models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma may be limited by life-history costs not present in susceptible counterparts. Schistosoma mansoni parasites from a praziquantel–susceptible (S), a praziquantel–resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond

Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs

Treatment with praziquantel (PZQ) has become virtually the sole basis of schistosomiasis control in sub-Saharan Africa and elsewhere, and the drug is reviewed here in the context of the increasing rate that it is being used for this purpose. Attention is drawn to our relative lack of knowledge about the mechanisms of action of PZQ at the molecular level, the need for more work to be done on schistosome isolates that have been collected recently from endemic areas rather than those maintained in laboratory conditions for long periods, and our reliance for experimental work mainly on Schistosoma mansoni, little work having been done on S. haematobium. There is no evidence that resistance to PZQ has been induced in African schistosomes as a result of its large-scale use on that continent to date, but there is also no assurance that PZQ and/or schistosomes are in any way unique and that resistant organisms will not be selected as a result of widespread drug usage. The failure of PZQ to produce complete cures in populations given a routine treatment should therefore solicit considerable concern. With few alternatives to PZQ currently available and/or on the horizon, methods to monitor drug-susceptibility in African schistosomes need to be devised and used to help ensure that this drug remains effective for as long a time as possibl

The Infectious Disease Ontology in the Age of COVID-19

The Infectious Disease Ontology (IDO) is a suite of interoperable ontology modules that aims to provide coverage of all aspects of the infectious disease domain, including biomedical research, clinical care, and public health. IDO Core is designed to be a disease and pathogen neutral ontology, covering just those types of entities and relations that are relevant to infectious diseases generally. IDO Core is then extended by a collection of ontology modules focusing on specific diseases and pathogens. In this paper we present applications of IDO Core within various areas of infectious disease research, together with an overview of all IDO extension ontologies and the methodology on the basis of which they are built. We also survey recent developments involving IDO, including the creation of IDO Virus; the Coronaviruses Infectious Disease Ontology (CIDO); and an extension of CIDO focused on COVID-19 (IDO-CovID-19).We also discuss how these ontologies might assist in information-driven efforts to deal with the ongoing COVID-19 pandemic, to accelerate data discovery in the early stages of future pandemics, and to promote reproducibility of infectious disease research

Patent Landscape of Helminth Vaccines and Related Technologies

Executive Summary This report focuses on patent landscape analysis of technologies related to vaccines targeting parasitic worms, also known as helminths. These technologies include methods of formulating vaccines, methods of producing of subunits, the composition of complete vaccines, and other technologies that have the potential to aid in a global response to this pathogen. The purpose of this patent landscape study was to search, identify, and categorize patent documents that are relevant to the development of vaccines that can efficiently promote the development of protective immunity against helminths. The search strategy used keywords which the team felt would be general enough to capture (or “recall”) the majority of patent documents which were directed toward vaccines against helminths. After extensive searching of patent literature databases, approximately 2847 publications were identified and collapsed to about 446 INPADOC families. Relevant patent families, almost half of the total relevant families (210 being total number of relevant families), were then identified and sorted into the categories of trematodes, cestodes, nematodes or nonspecific helminth. The 210 patent families that were divided into these four major categories were then further divided into sub categories relating to common fields of technology (e.g. DNA vaccine, vaccine formulations, methods to produce subunits) This sorting process increased the precision of the result set. The four major categories (cestodes, nematodes, trematodes, and non specific applications) as well as the overall data set of the 210 relevant family members were subjected to a range of analytics in order to extract as much information as possible from the dataset. First, patent landscape maps were generated to assess the accuracy of the sorting procedure and to reveal the relationships between the various technologies that are involved in creating an effective vaccine. Then, filings trends are analyzed for the overall dataset of the 210 relevant families as well as by the categories of trematodes, cestodes, and nematodes. The country of origin each member of the 210 relevant families was determined, and the range of distribution to other jurisdictions was assessed. Filings were also analyzed by year, by assignee. Finally, the various patent classification systems were mapped to find which particular classes tend to hold helminth vaccine-related technologies. Besides the keywords developed during the searches and the landscape map generation, the classifications represent an alternate way for further researchers to identify emerging helminth vaccine technologies. The analysis included creation of a map of keywords describing the relationship of the various technologies involved in the development of helminth vaccines. The map has regions corresponding to plasmids and other gene based technologies used in DNA vaccines for Japonicum Schistosoma. Important technologies listed on the map include the use of reverse genetics to create reassorted viruses targeted for the use in veterinary applications. Additionally, the map suggests that numerous subunits exist for use in vaccines targeting cestodes, trematodes, and nematodes. Another major finding was that the number of patent documents related to helminths being published has been steadily increasing in the last decade, as shown in the figure below. Until the early-1990s, there were only a few helminth vaccine related patent documents being published each year. The number of publications increased noticeably when TRIPS took effect, resulting in publication of patent applications. However, since 2006 the number of vaccine publications has exploded. In the years 2011 and 2012, about 23 references disclosing parasitic worm vaccine technologies were published each year. Thus, interest in developing new and more efficacious helminth vaccines has been growing in recent years. The origin of the vaccine-related inventions was also analyzed. The team determined the country in which the priority application was filed, which was taken as an indication of the country where the invention was made or where the inventors intended to practice the invention. By far, most of the relevant families originated with patent applications filed in the United States and China. Other prominent priority countries were the United Kingdom, Japan, Brazil, Australia and France. Countries with the most filings were also analyzed. Countries that were heavily targeted for patent filings included the United States, Australia, Canada, and New Zealand. Top assignees for these families were mostly large pharmaceutical companies, with the majority of patent families coming from Heska, followed by Merck & Co., Institute Pasteur, AusBiotech Biotechnology, and Biological Sciences Research Council. Lastly, the jurisdictions were inventors have sought protection for their vaccine technologies were determined, and the number of patent families filing in a given country is plotted on the world map shown (Fig. 25). The United States, Canada, Australia, Japan, New Zealand and France have the highest level of filings, followed by Germany, Brazil, India, United Kingdom and Spain. However, although there are a significant number of filings in Brazil, the remainder of Central and South America has only sparse filings. Of concern, with the exception of South Africa, few other African nations have a significant number of filings. In summary, the goal of this report is to provide a knowledge resource for making informed policy decisions and for creating strategic plans concerning the assembly of vaccines targeting highly prevalent helminth infections. The ITTI team has defined the current state of the art of technologies involved in the manufacture of helminth vaccines, and the important assignees, inventors, and countries have been identified. This document should aid in evaluating the current state of vaccines technologies targeting helminths and the potential outgrows of these technological fields. Furthermore, as this report illustrates, the steady increase in helminth patenting, expanded diversity of assignees and greater global filings, indicates that intellectual property protection does not inhibit the development of crucial innovations for this class of neglected diseases, but, on the contrary, appears to be a driver of accelerated research and development

Human Schistosome Infection and Allergic Sensitisation

Several field studies have reported an inverse relationship between the prevalence of helminth infections and that of allergic sensitisation/atopy. Recent studies show that immune responses induced by helminth parasites are, to an extent, comparable to allergic sensitisation. However, helminth products induce regulatory responses capable of inhibiting not only antiparasite immune responses, but also allergic sensitisation. The relative effects of this immunomodulation on the development of protective schistosome-specific responses in humans has yet to be demonstrated at population level, and the clinical significance of immunomodulation of allergic disease is still controversial. Nonetheless, similarities in immune responses against helminths and allergens pose interesting mechanistic and evolutionary questions. This paper examines the epidemiology, biology and immunology of allergic sensitisation/atopy, and schistosome infection in human populations