Effective vaccines are available for many protozoal diseases of animals, including vaccines for zoonotic pathogens and for several species of vector-transmitted apicomplexan haemoparasites. In comparison with human diseases, vaccine development for animals has practical advantages such as the ability to perform experiments in the natural host, the option to manufacture some vaccines in vivo, and lower safety requirements. Although it is proper for human vaccines to be held to higher standards, the enduring lack of vaccines for human protozoal diseases is difficult to reconcile with the comparatively immense amount of research funding. Common tactical problems of human protozoal vaccine research include reliance upon adapted rather than natural animal disease models, and an overwhelming emphasis on novel approaches that are usually attempted in replacement of rather than for improvement upon the types of designs used in effective veterinary vaccines. Currently, all effective protozoal vaccines for animals are predicated upon the ability to grow protozoal organisms. Because human protozoal vaccines need to be as effective as animal vaccines, researchers should benefit from a comparison of existing veterinary products and leading experimental vaccine designs. With this in mind, protozoal vaccines are here reviewed.

The melanotic encapsulation response mounted by Drosophila melanogaster against macroparasites, which is based on haemocyte binding to foreign objects, is poorly characterized relative to its humoral immune response against microbes, and appears to be variable across insect lineages. The genus Zaprionus is a diverse clade of flies embedded within the genus Drosophila. Here we characterize the immune response of Zaprionus indianus against endoparasitoid wasp eggs, which elicit the melanotic encapsulation response in D. melanogaster. We find that Z. indianus is highly resistant to diverse wasp species. Although Z. indianus mounts the canonical melanotic encapsulation response against some wasps, it can also potentially fight off wasp infection using two other mechanisms: encapsulation without melanization and a non-cellular form of wasp killing. Zaprionus indianus produces a large number of haemocytes including nematocytes, which are large fusiform haemocytes absent in D. melanogaster, but which we found in several other species in the subgenus Drosophila. Several lines of evidence suggest these nematocytes are involved in anti-wasp immunity in Z. indianus and in particular in the encapsulation of wasp eggs. Altogether, our data show that the canonical anti-wasp immune response and haemocyte make-up of the model organism D. melanogaster vary across the genus Drosophila.

Plasmodium falciparum malaria is responsible for over 250 million clinical cases every year worldwide. Severe malaria cases might present with a range of disease syndromes including acute respiratory distress, metabolic acidosis, hypoglycaemia, renal failure, anaemia, pulmonary oedema, cerebral malaria (CM) and placental malaria (PM) in pregnant women. Two main determinants of severe malaria have been identified: sequestration of parasitized red blood cells and strong pro-inflammatory responses. Increasing evidence from human studies and malaria infection animal models revealed the presence of host leucocytes at the site of parasite sequestration in brain blood vessels as well as placental tissue in complicated malaria cases. These observations suggested that apart from secreting cytokines, leucocytes might also contribute to disease by migrating to the site of parasite sequestration thereby exacerbating organ-specific inflammation. This evidence attracted substantial interest in identifying trafficking pathways by which inflammatory leucocytes are recruited to target organs during severe malaria syndromes. Chemo-attractant cytokines or chemokines are the key regulators of leucocyte trafficking and their potential contribution to disease has recently received considerable attention. This review summarizes the main findings to date, investigating the role of chemokines in severe malaria and the implication of these responses for the induction of pathogenesis and immunity to infection.

From hundreds of independent transitions from a free-living existence to a parasitic mode of life, separate parasite lineages have converged over evolutionary time to share traits and exploit their hosts in similar ways. Here, we first summarize the evidence that, at a phenotypic level, eukaryotic parasite lineages have all converged toward only six general parasitic strategies: parasitoid, parasitic castrator, directly transmitted parasite, trophically transmitted parasite, vector-transmitted parasite or micropredator. We argue that these strategies represent adaptive peaks, with the similarities among unrelated taxa within any strategy extending to all basic aspects of host exploitation and transmission among hosts and transcending phylogenetic boundaries. Then, we extend our examination of convergent patterns by looking at the evolution of parasite genomes. Despite the limited taxonomic coverage of sequenced parasite genomes currently available, we find some evidence of parallel evolution among unrelated parasite taxa with respect to genome reduction or compaction, and gene losses or gains. Matching such changes in parasite genomes with the broad phenotypic traits that define the convergence of parasites toward only six strategies of host exploitation is not possible at present. Nevertheless, as more parasite genomes become available, we may be able to detect clear trends in the evolution of parasitic genome architectures representing true convergent adaptive peaks, the genomic equivalents of the phenotypic strategies used by all parasites.

The cumulative effect of co-infections between pathogen pairs on the haematological response of East African Short-horn Zebu calves is described. Using a longitudinal study design a stratified clustered random sample of newborn calves were recruited into the Infectious Diseases of East African Livestock (IDEAL) study and monitored at 5-weekly intervals until 51 weeks of age. At each visit samples were collected and analysed to determine the infection status of each calf as well as their haematological response. The haematological parameters investigated included packed cell volume (PCV), white blood cell count (WBC) and platelet count (Plt). The pathogens of interest included tick-borne protozoa and rickettsias, trypanosomes and intestinal parasites. Generalized additive mixed-effect models were used to model the infectious status of pathogens against each haematological parameter, including significant interactions between pathogens. These models were further used to predict the cumulative effect of co-infecting pathogen pairs on each haematological parameter. The most significant decrease in PCV was found with co-infections of trypanosomes and strongyles. Strongyle infections also resulted in a significant decrease in WBC at a high infectious load. Trypanosomes were the major cause of thrombocytopenia. Platelet counts were also affected by interactions between tick-borne pathogens. Interactions between concomitant pathogens were found to complicate the prognosis and clinical presentation of infected calves and should be taken into consideration in any study that investigates disease under field conditions.

This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic–pharmacodynamic (PK–PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic–pharmacodyamic studies in animal infection models.

The co-occurrence of different pathogen species and their simultaneous infection of hosts are common, and may affect host health outcomes. Co-infecting pathogens may interact synergistically (harming the host more) or antagonistically (harming the host less) compared with single infections. Here we have tested associations of infections and their co-infections with variation in growth rate using a subset of 455 animals of the Infectious Diseases of East Africa Livestock (IDEAL) cohort study surviving to one year. Data on live body weight, infections with helminth parasites and haemoparasites were collected every 5 weeks during the first year of life. Growth of zebu cattle during the first year of life was best described by a linear growth function. A large variation in daily weight gain with a range of 0·03–0·34 kg, and a mean of 0·135 kg (0·124, 0·146; 95% CI) was observed. After controlling for other significant covariates in mixed effects statistical models, the results revealed synergistic interactions (lower growth rates) with Theileria parva and Anaplasma marginale co-infections, and antagonistic interactions (relatively higher growth rates) with T. parva and Theileria mutans co-infections, compared with infections with T. parva only. Additionally, helminth infections can have a strong negative effect on the growth rates but this is burden-dependent, accounting for up to 30% decrease in growth rate in heavily infected animals. These findings present evidence of pathogen–pathogen interactions affecting host growth, and we discuss possible mechanisms that may explain observed directions of interactions as well as possible modifications to disease control strategies when co-infections are present.

In the eastern Tibetan plateau both human cystic and alveolar echinococcosis (AE) caused by infection with Echincoccus granulosus or Echinococcus multilocularis, respectively are highly endemic. The domestic dog plays a key role in zoonotic transmission in this region. Our primary objective was to investigate the role of domestic dogs in maintaining transmission of E. multilocularis in Shiqu county, Sichuan. A cohort of 281 dogs was followed up over one year after a single treatment with praziquantel followed by re-infection surveillance at 2, 5 and 12 months post-treatment. Faecal samples were tested by an Echinococcus genus-specific coproantigen ELISA and two species-specific copro-PCR tests. Total Echinococcus coproantigen prevalence in Shiqu at baseline was 21% and 9·6% after 2 months. E. multilocularis copro-PCR was positive in 11·2% of dogs before treatment (vs 3·6% with E. granulosus copro-DNA), 2·9% at 2 months post-treatment, and 0% at 5 month and 12 months. The results suggest that dogs may have the potential to maintain E. multilocularis transmission within local pastoral communities, and thus dog dosing could be an effective strategy to reduce transmission of E. multilocularis as well as E. granulosus in these co-endemic Tibetan communities.

Open science is a new concept for the practice of experimental laboratory-based research, such as drug discovery. The authors have recently gained experience in how to run such projects and here describe some straightforward steps others may wish to take towards more openness in their own research programmes. Existing and inexpensive online tools can solve many challenges, while some psychological barriers to the free sharing of all data and ideas are more substantial.

Echinococcosis is a re-emerging zoonotic disease in Kyrgyzstan, and the incidence of human infection has increased substantially since the collapse of the Soviet Union in 1991. Domestic dogs are hosts of Echinococcus spp. and play an important role in the transmission of these parasites. The demography, ecology and behaviour of dogs are therefore relevant in studying Echinococcus spp. transmission. Dog demographics, roles of dogs, dog movements and faecal environmental contamination were assessed in four rural communities in the Alay Valley, southern Kyrgyzstan. Arecoline purge data revealed for the first time that E. granulosus, E. canadensis and E. multilocularis were present in domestic dogs in the Alay Valley. Surveys revealed that many households had dogs and that dogs played various roles in the communities, as pets, guard dogs or sheep dogs. Almost all dogs were free to roam, and GPS data revealed that many moved outside their communities, thus being able to scavenge offal and consume rodents. Faecal environmental contamination was high, presenting a significant infection risk to the local communities.

The mouse whipworm Trichuris muris has long been used as a tractable model of human Trichuriasis. Here we look back at the history of T. muris research; from the definition of the species and determination of its life cycle, through to the complex immune responses that we study today. We highlight the key research papers that have developed our understanding of immune responses to this parasite, and reflect on how original concepts have been transformed, as our knowledge of immunology has grown. Although we have a good understanding of host–parasite interactions in the context of the underlying cellular immunology, there are still many aspects of the biology of the Trichuris parasite that remain undefined. We predict that advances in parasite biology will be key in the future development of new and improved treatments for Trichuriasis.

Dogs infected with Angiostrongylus vasorum, a potentially lethal parasite parasitizing the heart and pulmonary arteries, may present severe respiratory, haematological and neurological signs. In this first large-scale seroepidemiological survey, 4003 sera originating from Germany and 4030 from the UK were tested by an ELISA for the detection of circulating antigen of A. vasorum, and by a separate ELISA detecting specific antibodies. In Germany, where mainly western federal states were sampled, 0·3% (n = 13, CI: 0·2–0·6%) of dogs were positive in both ELISAs, whereas in total 0·5% (n = 20, CI: 0·3–0·8%) were antigen-positive and 2·25% (n = 90, CI: 1·8–2·8%) were positive for specific antibodies. Regions with antigen- and antibody-positive animals were overlapping. In the UK, where mainly the south of the country was sampled, 0·97% (n = 39, CI: 0·7–1·3%) of dogs were antigen- and antibody positive. In total, 1·32% (n = 53, CI: 1·0–1·7%) were antigen-positive, and 3·2% (n = 129, CI: 2·7–3·8%) were positive for specific antibodies, again in overlapping regions. These results confirm the occurrence of A. vasorum in a random dog population originating from large parts of the countries investigated. The use of the tests alone or in combination was considered as a function of their sensitivities and specificities, in order to guide efficient clinical and epidemiological application.

Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.

Anti-Wolbachia therapy delivers safe macrofilaricidal activity with superior therapeutic outcomes compared to all standard anti-filarial treatments, with the added benefit of substantial improvements in clinical pathology. These outcomes can be achieved, in principle, with existing registered drugs, e.g. doxycycline, that are affordable, available to endemic communities and have well known, albeit population-limiting, safety profiles. The key barriers to using doxycycline as an mass drug administration (MDA) strategy for widespread community-based control are the logistics of a relatively lengthy course of treatment (4–6 weeks) and contraindications in children under eight years and pregnancy. Therefore, the primary goal of the anti-Wolbachia (A·WOL) consortium is to find drugs and regimens that reduce the period of treatment from weeks to days (7 days or less), and to find drugs which would be safe in excluded target populations (pregnancy and children). A secondary goal is to refine regimens of existing antibiotics suitable for a more restricted use, prior to the availability of a regimen that is compatible with MDA usage. For example, for use in the event of the emergence of drug-resistance, in individuals with high loiasis co-infection and at risk of severe adverse events (SAE) to ivermectin, or in post-MDA ‘endgame scenarios’, where test and treat strategies become more cost effective and deliverable.

Malaria is a disease that still affects a significant proportion of the global human population. Whilst advances have been made in lowering the numbers of cases and deaths, it is clear that a strategy based solely on disease control year on year, without reducing transmission and ultimately eradicating the parasite, is unsustainable. This article highlights the current mainstay treatments alongside a selection of emerging new clinical molecules from the portfolio of Medicines for Malaria Venture (MMV) and our partners. In each case, the key highlights from each research phase are described to demonstrate how these new potential medicines were discovered. Given the increased focus of the community on eradicating the disease, the strategy for next generation combination medicines that will provide such potential is explained.

The discovery, development and optimal utilization of pharmaceuticals can be greatly enhanced by knowledge of their modes of action. However, many drugs currently on the market act by unknown mechanisms. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Development of high resolution LC-MS methods and improved data analysis software now allows rapid detection of drug-induced changes to cellular metabolism in an untargeted manner. Several studies have demonstrated the ability of untargeted metabolomics to provide unbiased target discovery for antimicrobial drugs, in particular for antiprotozoal agents. Furthermore, the utilization of targeted metabolomics techniques has enabled validation of existing hypotheses regarding antiprotozoal drug mechanisms. Metabolomics approaches are likely to assist with optimization of new drug candidates by identification of drug targets, and by allowing detailed characterization of modes of action and resistance of existing and novel antiprotozoal drugs.

From continental to regional scales, the zoonosis alveolar echinococcosis (AE) (caused by Echinococcus multilocularis) forms discrete patches of endemicity within which transmission hotspots of much larger prevalence may occur. Since the late 80s, a number of hotspots have been identified in continental Asia, mostly in China, wherein the ecology of intermediate host communities has been described. This is the case in south Gansu, at the eastern border of the Tibetan plateau, in south Ningxia, in the western Tian Shan of Xinjiang, and in the Alay valley of south Kyrgyzstan. Here we present a comparative natural history and characteristics of transmission ecosystems or ecoscapes. On this basis, regional types of transmission and their ecological characteristics have been proposed in a general framework. Combining climatic, land cover and intermediate host species distribution data, we identified and mapped 4 spatially distinct types of transmission ecosystems typified by the presence of one of the following small mammal ‘flagship’ species: Ellobius tancrei, Ochotona curzoniae, Lasiopodomys brandtii or Eospalax fontanierii. Each transmission ecosystem had its own characteristics which can serve as a reference for further in-depth research in the transmission ecology of E. multilocularis. This approach may be used at fine spatial scales to characterize other poorly known transmission systems of the large Eurasian endemic zone, and help in consideration of surveillance systems and interventions.

Parasitic helminths are ubiquitous in most host, including human, populations. Helminths often alter the likelihood of infection and disease progression of coinfecting microparasitic pathogens (viruses, bacteria, protozoa), and there is great interest in incorporating deworming into control programmes for many major diseases (e.g. HIV, tuberculosis, malaria). However, such calls are controversial; studies show the consequences of deworming for the severity and spread of pathogens to be highly variable. Hence, the benefits of deworming, although clear for reducing the morbidity due to helminth infection per se, are unclear regarding the outcome of coinfections and comorbidities. I develop a theoretical framework to explore how helminth coinfection with other pathogens affects host mortality and pathogen spread and evolution under different interspecific parasite interactions. In all cases the outcomes of coinfection are highly context-dependent, depending on the mechanism of helminth-pathogen interaction and the quantitative level of helminth infection, with the effects of deworming potentially switching from beneficial to detrimental depending on helminth burden. Such context-dependency may explain some of the variation in the benefits of deworming seen between studies, and highlights the need for obtaining a quantitative understanding of parasite interactions across realistic helminth infection ranges. However, despite this complexity, this framework reveals predictable patterns in the effects of helminths that may aid the development of more effective, integrated management strategies to combat pathogens in this coinfected world.

The trypanosomes cause two neglected tropical diseases, Chagas disease in the Americas and African trypanosomiasis in sub-Saharan Africa. Over recent years a raft of molecular tools have been developed enabling the genetic dissection of many aspects of trypanosome biology, including the mechanisms underlying resistance to some of the current clinical and veterinary drugs. This has led to the identification and characterization of key resistance determinants, including transporters for the anti-Trypanosoma brucei drugs, melarsoprol, pentamidine and eflornithine, and the activator of nifurtimox-benznidazole, the anti-Trypanosoma cruzi drugs. More recently, advances in sequencing technology, combined with the development of RNA interference libraries in the clinically relevant bloodstream form of T. brucei have led to an exponential increase in the number of proteins known to interact either directly or indirectly with the anti-trypanosomal drugs. In this review, we discuss these findings and the technological developments that are set to further revolutionise our understanding of drug-trypanosome interactions. The new knowledge gained should inform the development of novel interventions against the devastating diseases caused by these parasites.

Identification of the major loci responsible for insecticide resistance in malaria vectors would aid the development and implementation of effective resistance management strategies, which are urgently needed to tackle the growing threat posed by resistance to the limited insecticides available for malaria control. Genome-wide association studies in the major malaria vector, Anopheles gambiae, have been hindered by the high degree of within-population structuring and very low levels of linkage disequilibrium hence we revisited the use of quantitative trait loci (QTL) mapping to study resistance phenotypes in this vector species. Earlier work, identified two major QTL associated with pyrethroid resistance in A. gambiae s.s. from East Africa using genetic crossing of laboratory-colonized resistant and susceptible strains. In this study, we report the results from genetic mapping of pyrethroid resistance in three isofemale pedigrees established from wild-caught female A. gambiae s.s. mosquitoes from Benin. We identified two QTL on chromosomes 2L and 3R in these field populations, in similar genomic locations to the QTL identified in laboratory strains. The relative merits of two alternative study designs are discussed and suggestions made for future genetic mapping studies of insecticide resistance in mosquitoes.