Parasite Tolerance Research Articles

Antimalarial Activity of Nigella sativa L. Seed Extracts and Selection of Resistance in Plasmodium berghei ANKA in a Mouse Model.

Background Chemotherapy plays a crucial role in malaria control. However, the main obstacle to treatment has been the rise of parasite resistance to most antimalarial drugs. Artemisinin-based combination therapies (ACTs) remain the most effective antimalarial medicines available today. However, malaria parasite tolerance to ACTs is now increasingly prevalent especially in Southeast Asia presenting the danger of the spread of ACTs resistance to other parts of the world. Consequently, this creates the need for alternative effective antimalarials. Therefore, this study sought out to determine antimalarial potential, safety, and resistance development of the extracts in a mouse model. Method Methanolic and ethyl acetate extracts were obtained by solvent extraction. The extracts were assayed for acute toxicity in vivo. Additionally, the two extracts were evaluated for antimalarial activity in vivo against Plasmodium berghei ANKA strain by the 4-day suppressive test at 500, 250, and 125 mg/kg/day. Packed cell volume was evaluated to determine anemia manifestation. Finally, continuous drug pressure experiment at 500 mg/kg and DNA amplification via PCR were conducted. The amplicons underwent through Sanger sequencing. Results There was no toxicity realized in the animals at 2000 mg/kg. Importantly, high parasitemia suppression of 75.52% and 75.30% using a dose of 500 mg/kg of methanolic and ethyl acetate extracts, respectively, was noted. The extracts were able to reverse packed cell volume reduction. Nigella sativa-resistant phenotype was selected as delayed parasite clearance. However, there was no change in the nucleotide sequences of PbMDR1 and PbCRT genes. Conclusion The results provide room for future exploitation of the plant as an antimalarial.

The application of community ecology theory to co-infections in wildlife hosts.

Priority effect theory, a foundational concept from community ecology, states that the order and timing of species arrival during species assembly can affect species composition. Although this theory has been applied to co-infecting parasite species, it has almost always been with a single time lag between co-infecting parasites. Thus, how the timing of parasite species arrival affects co-infections and disease remains poorly understood. To address this gap in the literature, we exposed postmetamorphic Cuban tree frogs (Osteopilus septentrionalis) to Ranavirus, the fungus Batrachochytrium dendrobatidis (Bd), a nematode Aplectana hamatospicula, or pairs of these parasites either simultaneously or sequentially at a range of time lags and quantified load of the secondary parasite and host growth, survival, and parasite tolerance. Prior exposure to Bd or A. hamatospicula significantly increased viral loads relative to hosts singly infected with Ranavirus, whereas A. hamatospicula loads in hosts were higher when coexposed to Bd than when coexposed to Ranavirus. There was a significant positive relationship between time since Ranavirus infection and Bd load, and prior exposure to A. hamatospicula decreased Bd loads compared to simultaneous co-infection with these parasites. Infections with Bd and Ranavirus either singly or in co-infections decreased host growth and survival. This research reveals that time lags between co-infections can affect parasite loads, in line with priority effects theory. As co-infections in the field are unlikely to be simultaneous, an understanding of when co-infections are impacted by time lags between parasite exposures may play a major role in controlling problematic co-infections.

The Role of Microbiome and Genotype in Daphnia magna upon Parasite Re-Exposure.

Recently, it has been shown that the community of gut microorganisms plays a crucial role in host performance with respect to parasite tolerance. Knowledge, however, is lacking on the role of the gut microbiome in mediating host tolerance after parasite re-exposure, especially considering multiple parasite infections. We here aimed to fill this knowledge gap by studying the role of the gut microbiome on tolerance in Daphnia magna upon multiple parasite species re-exposure. Additionally, we investigated the role of the host genotype in the interaction between the gut microbiome and the host phenotypic performance. A microbiome transplant experiment was performed in which three germ-free D. magna genotypes were exposed to a gut microbial inoculum and a parasite community treatment. The gut microbiome inocula were pre-exposed to the same parasite communities or a control treatment. Daphnia performance was monitored, and amplicon sequencing was performed to characterize the gut microbial community. Our experimental results showed that the gut microbiome plays no role in Daphnia tolerance upon parasite re-exposure. We did, however, find a main effect of the gut microbiome on Daphnia body size reflecting parasite specific responses. Our results also showed that it is rather the Daphnia genotype, and not the gut microbiome, that affected parasite-induced host mortality. Additionally, we found a role of the genotype in structuring the gut microbial community, both in alpha diversity as in the microbial composition.

Tolerance of liver fluke infection varies between breeds and producers in beef cattle

Liver flukes (Fasciola spp.) are important helminth parasites of livestock globally and cause substantial reductions in health and productivity of beef cattle. Attempts to control fluke have been thwarted by the difficulty of vaccine design, the evolution of flukicide resistance and the need to control the intermediate snail host. Mechanisms to reduce the impact of parasites on animal performance have typically focused on promoting host resistance – defined as the ability of the host to kill and remove the parasite from its system – and such strategies include improving protein nutrition or selective breeding for resistance. Organisms, however, have another broad mechanism for mitigating the impact of parasites: they can show tolerance, defined as the ability to maintain health or performance under increasing parasite burden. Tolerance has been studied in the plant literature for over a century, but there are very few empirical studies of parasite tolerance in livestock. In this study, we used data collected from >90 000 beef cattle to estimate the impact of the severity of liver fluke infection on performance and variation in tolerance of fluke. Severity of liver fluke infection was estimated using liver “fibrosis score” on a scale of 0–3 and performance estimated as (1) age at slaughter and (2) daily dead weight gain. Animals with higher fibrosis scores were slaughtered around 2 weeks later than animals with no fluke and gained around 10 g less weight per day. There was also considerable variation in these effects of fibrosis score, such that animals from different producers and breeds varied in their tolerance of fluke infection. While breeds did not vary in the association between fibrosis and age at slaughter, there was considerable variation among producers: high fibrosis score delayed slaughter by up to 50 days in some producers, but not at all in others. Meanwhile, there was support for variation in the slope of daily dead weight gain on fibrosis score among both breeds and producers, with some unaffected by high fluke scores and some breeds and producers experiencing a 20 g/day lower weight gain under high fluke scores. Our results point to the potential for both environmental and genetic variation in tolerance of liver fluke in cattle, paving the way for quantitative genetic and nutritional research into the feasibility of promoting tolerance as a disease mitigation strategy.

Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing.

ABSTRACTStudies of the susceptibility of Plasmodium falciparum to the artemisinin family of antimalarial drugs provide a complex picture of partial resistance (tolerance) associated with increased parasite survival in vitro and in vivo. We present an overview of the genetic loci that, in mutant form, can independently elicit parasite tolerance. These encode Kelch propeller domain protein PfK13, ubiquitin hydrolase UBP-1, actin filament-organising protein Coronin, also carrying a propeller domain, and the trafficking adaptor subunit AP-2μ. Detailed studies of these proteins and the functional basis of artemisinin tolerance in blood-stage parasites are enabling a new synthesis of our understanding to date. To guide further experimental work, we present two major conclusions. First, we propose a dual-component model of artemisinin tolerance in P. falciparum comprising suppression of artemisinin activation in early ring stage by reducing endocytic haemoglobin capture from host cytosol, coupled with enhancement of cellular healing mechanisms in surviving cells. Second, these two independent requirements limit the likelihood of development of complete artemisinin resistance by P. falciparum, favouring deployment of existing drugs in new schedules designed to exploit these biological limits, thus extending the useful life of current combination therapies.

Evolutionarily stable investments in recognition systems explain patterns of discrimination failure and success.

Many animals are able to perform recognition feats that astound us-such as a rodent recognizing kin it has never met. Yet in other contexts, animals appear clueless as when reed warblers rear cuckoo chicks that bear no resemblance to their own species. Failures of recognition when it would seem adaptive have been especially puzzling. Here, we present a simple tug-of-war game theory model examining how individuals should optimally invest in affecting the accuracy of discrimination between desirable and undesirable recipients. In the game, discriminating individuals (operators) and desirable and undesirable recipients (targets and mimics, respectively) can all invest effort into their own preferred outcome. We demonstrate that stable inaccurate recognition will arise when undesirable recipients have large fitness gains from inaccurate recognition relative to the pay-offs that the other two parties receive from accurate recognition. The probability of accurate recognition is often determined by just the relative pay-offs to the desirable and undesirable recipients, rather than to the discriminator. Our results provide a new lens on long-standing puzzles including a lack of nepotism in social insect colonies, tolerance of brood parasites and male birds caring for extra-pair young in their nests, which our model suggests should often lack accurate discrimination. This article is part of the theme issue 'Signal detection theory in recognition systems: from evolving models to experimental tests'.

Negative associations between parasite avoidance, resistance and tolerance predict host health in salmonid fish populations.

Genetic variation in defence against parasite infections is fundamental for host-parasite evolution. The overall level of defence of a host individual or population includes mechanisms that reduce parasite exposure (avoidance), establishment (resistance) or pathogenicity (tolerance). However, how these traits operate and evolve in concert is not well understood. Here, we investigated genetic variation in and associations between avoidance, resistance and tolerance in a natural host-parasite system. Replicated populations of Atlantic salmon (Salmo salar) and sea trout (an anadromous form of brown trout, Salmo trutta) were raised under common garden conditions and infected with the eye fluke Diplostomum pseudospathaceum. We demonstrate significant genetic variation in the defence traits across host populations and negative associations between the traits, with the most resistant populations showing the weakest avoidance and the lowest infection tolerance. These results are suggestive of trade-offs between different components of defence and possibly underlie the genetic variation in defence traits observed in the wild. Because the three defence mechanisms affect host-parasite evolution in profoundly different ways, we emphasize the importance of studying these traits in concert.

Context-Dependence in parasite effects on keyhole limpets

Parasites alter the reproductive performance of their hosts, limit their growth, and thereby modify the energy budget of these hosts. Experimental studies and theoretical models suggest that the outcome of the host-parasite interactions could be determined by ecological factors such as food availability levels in the local habitats. Nutrient inputs may affect the host's food resource availability with positive or negative effects on parasite infection rates and tolerance of infection, however this has not been specifically evaluated in natural systems. In this study, we evaluate the effects of parasitism by Proctoeces humboldti on body size, gonadosomatic index (GSI), and metabolic rate (oxygen consumption) of their second intermediate host Fissurella crassa limpets, under contrasting natural conditions of productivity (upwelling center vs upwelling shadow sites). Our results evidenced that parasitized limpets collected from the intertidal habitat influenced by coastal upwelling site showed greater shell length, muscular foot biomass and GSI as compared to non-parasitized limpets collected in the same site, and compared to parasitized and non-parasitized limpets collected from the sites under the influence of upwelling shadow conditions. Oxygen consumption was lower in parasitized limpets collected from the upwelling-influenced site than in the other groups, independent of age, suggesting reduced metabolic stress in infected individuals inhabiting these productive sites. Our results suggest that increased productivity in upwelling sites could mitigate the conflict for resources in the P. humboldti – F. crassa system, influencing where such interaction is found in the continuum between parasitism and mutualism. Since parasitism is ubiquitous in natural systems, and play important roles in ecological and evolutionary processes, it is important to analyze host-parasite interaction across a variety of ecological conditions, especially in biological conservation.

Cattle adapted to tropical and subtropical environments: genetic and reproductive considerations

Efforts to understand biological functions and develop management schemes specific to Bos indicus-influenced cattle raised in tropical and subtropical environments are critical to meet the increasing global demand for protein. In the United States, B. indicus breeds are mostly used to generate B. indicus × B. taurus crosses with increased thermal and parasite tolerance, while retaining some productive characteristics of B. taurus cattle. Although crossbreeding represents a proven strategy to improve cattle adaptation almost immediately, research has also attempted to identify B. taurus genetics that can withstand subtropical and tropical climates. Reduced milk production and delayed reproductive maturation appear to be related with tropical adaptation of B. taurus breeds, as a means to conserve energy under stressful conditions and limited nutrition. Moreover, longevity may be the ultimate adaptation response to unfavorable environments, and retention of bulls and heifers from proven cows is the recommended strategy to improve longevity in B. indicus-influenced herds. Besides selection for longevity, other aspects should be considered when planning reproductive management in tropical and subtropical regions. Bos indicus and B. taurus breeds have multiple differences pertaining to reproductive function, including age at puberty, ovarian dynamics, and pregnancy development. Nutritional strategies such as the stair-step regimen, and use of exogenous progesterone (P4) inserts are options to hasten puberty attainment of late-maturing B. indicus-influenced heifers. Yet, limited pharmacological alternatives are available for reproductive management of B. indicus-influenced females in the United States, which rely on GnRH-based protocols not specifically designed to the reproductive function of B. indicus breeds. In contrast, hormonal protocols based on exogenous P4, estradiol esters, and equine chorionic gonadotropin are available for use in B. indicus females in South America. These include protocols tailored to prepubertal heifers, anestrous cows, and cycling nulliparous or parous females, which often yield pregnancy rates of 50% to fixed-time artificial insemination. The global dairy industry also faces similar challenges in increasing demand and production as the beef industry. Selection of cows capable of sustaining optimal milk yield, reproductive success, and health status in hot and humid conditions is essential for optimal dairy production in subtropical and tropical regions.

Changing plasma cytokine, chemokine and growth factor profiles upon differing malaria transmission intensities

BackgroundMalaria epidemiological and immunological data suggest that parasite tolerance wanes in the absence of continuous exposure to the parasite, potentially enhancing pathogenesis. The expansion of control interventions and elimination campaigns raises the necessity to better understand the host factors leading to susceptibility or tolerance that are affected by rapid changes in malaria transmission intensity (MTI). Mediators of cellular immune responses are responsible for the symptoms and pathological alterations during disease and are expected to change rapidly upon malaria exposure or cessation.MethodsThe plasma concentrations of 30 cytokine, chemokine and growth factors in individuals of all ages from a malaria endemic area of southern Mozambique were compared between 2 years of different MTI: 2010 (lower, n = 234) and 2013 (higher, n = 143). The effect of the year on the correlations between cytokines, chemokines and growth factors and IgGs to Plasmodium falciparum (markers of exposure) was explored. The effects of age, sex, neighbourhood and parasitaemia on analyte levels and their interactions with year were also assessed.ResultsAn inverse correlation of several cellular immune mediators with malarial antibodies in 2013, and a lack of correlation or even a positive correlation in 2010 were observed. Most cytokines, chemokines and growth factors, regardless of their immune function, had higher concentrations in 2010 compared with 2013 in P. falciparum-infected and uninfected subjects. Age and neighbourhood showed an effect on analyte concentrations.ConclusionsThe results show a different regulation of the cellular immune response in 2010 vs 2013 which could be related to a loss of immune-tolerance after a decline in MTI in 2010 and previous years, and a rapid re-establishment of tolerance as a consequence of more continuous exposure as MTI began increasing in 2012. Cellular immune mediators warrant further investigation as possible surrogates of MTI-associated host susceptibility or tolerance.

Variation in Tolerance to Parasites Affects Vectorial Capacity of Natural Asian Tiger Mosquito Populations.

Globally, diseases transmitted by arthropod vectors, such as mosquitoes, remain a major cause of morbidity and mortality [1]. The defense responses of mosquito and other arthropod vectors against parasites are important for understanding disease transmission dynamics and for the development of novel disease-control strategies. Consequently, the mechanisms by which mosquitoes resist parasitic infection (e.g., immune-mediated killing) have long been studied [2, 3]. However, the ability of mosquitoes to ameliorate the negative fitness consequences of infection through tolerance mechanisms (e.g., tissue repair) has been virtually ignored (but see [4, 5]). Ignoring parasite tolerance is especially taxing in vector biology because unlike resistance, which typically reduces vectorial capacity, tolerance is expected to increase vectorial capacity by reducing parasite-mediated mortality without killing parasites [6], contributing to the recurrent emergence of vector-borne diseases and its stabilization and exacerbation. Despite its importance, there is currently no evidence for the evolution of tolerance in natural mosquito populations. Here, we use a common-garden experimental framework to measure variation in resistance and tolerance to dog heartworm (Dirofilaria immitis) between eight natural Aedes albopictus mosquito populations representing areas of low and high transmission intensity. We find significant inter-population variation in tolerance and elevated tolerance where transmission intensity is high. Additionally, as expected, we find that increased tolerance is associated with higher vectorial capacity. Consequently, our results indicate that high transmission intensity can lead to the evolution of more competent disease vectors, which can feed back to impact disease risk.

Voltage Balance Switching Scheme for Series-Connected SiC MOSFET LLC Resonant Converter

To achieve high efficiency and power density, silicon carbide (SiC)-based Inductor-Inductor-Capacitor (LLC) resonant converters are applied to the DC/DC converter stage of a solid-state transformer (SST). However, because the input voltage of an SST is higher than the rated voltage of a commercial SiC device, it is essential to connect SiC devices in series. This structure is advantageous in terms of voltage rating, but a parasitic capacitance tolerance between series-connected SiC devices causes voltage imbalance. Such imbalance greatly reduces system stability as it causes overvoltage breakdown of SiC device. Therefore, this paper proposes a switching scheme to solve the voltage imbalance between SiC metal-oxide-semiconductor field-effect transistors (MOSFETs). The proposed scheme sequentially turns off series-connected SiC MOSFETs to compensate for the turn-off delays caused by parasitic capacitor tolerances. In addition, dead-time selection methods to achieve voltage balance and zero voltage switching simultaneously are provided in detail. To verify the effectiveness of the proposed scheme, experiments were conducted on a 2 kW series-connected SiC MOSFET LLC resonant converter prototype.

In vitro activity of ferroquine against artemisinin-based combination therapy (ACT)-resistant Plasmodium falciparum isolates from Cambodia.

Cambodia is the epicentre of resistance emergence for virtually all antimalarial drugs. Selection and spread of parasites resistant to artemisinin-based combination therapy (ACT) is a major threat for malaria elimination, hence the need to renew the pool of effective treatments. To determine whether ACT resistance haplotypes could have an effect on ferroquine in vitro antimalarial activity. In vitro susceptibility to ferroquine was measured for 80 isolates from Cambodia characterized for their molecular resistance profile to artemisinin, piperaquine and mefloquine. Among the 80 isolates tested, the overall median (IQR) IC50 of ferroquine was 10.9 nM (8.7-18.3). The ferroquine median (IQR) IC50 was 8.9 nM (8.1-11.8) for Pfk13 WT parasites and was 12.9 nM (9.5-20.0) for Pfk13 C580Y parasites with no amplification of Pfpm2 and Pfmdr1 genes. The median (IQR) IC50 of ferroquine for Pfk13 C580Y parasites with amplification of the Pfpm2 gene was 17.2 nM (14.5-20.5) versus 9.1 nM (7.9-10.7) for Pfk13 C580Y parasites with amplification of the Pfmdr1 gene. Ferroquine exerts promising efficacy against ACT-resistant isolates. Whereas Pfpm2 amplification was associated with the highest parasite tolerance to ferroquine, the susceptibility range observed was in accordance with those measured in ACT resistance-free areas. This enables consideration of ferroquine as a relevant therapeutic option against ACT-resistant malaria.

Coevolutionary arms race between a specialist brood parasite, the Screaming Cowbird, and its host, the Grayish Baywing

Interspecific brood parasites exploit the parental care of host species. This exploitation entails fitness costs for the hosts, which favor the evolution of antiparasitic defenses. Host defenses select for counter-defenses in the parasite, which in turn select for improved host defenses; this results in a coevolutionary arms race that may operate at each stage of the nesting cycle of the host. Most studied examples of the coevolutionary arms race in brood parasites are restricted to the egg stage, with relatively few studies showing coevolution between hosts and parasites at the nestling or fledgling stages; studies on the whole set of host defenses and potential parasite counter-defenses at each stage of the breeding cycle are still lacking. Systems in which parasites are host specialists are particularly well suited to an examination of the pairwise coevolutionary interactions before, during and after host egg-laying, and how these interactions have shaped host resistance or tolerance of parasitism. The Screaming Cowbird (Molothrus rufoaxillaris) is one of the most specialized brood parasites, and mainly parasitizes nests of a single host species, the Grayish Baywing (Agelaioides badius). Parasitism rates of Grayish Baywing nests are extremely high, with most nests parasitized several times. Several traits of this host-parasite system suggest ancient coevolutionary relationships encompassing the entire nesting cycle. In this paper we summarize the main results of a long-term study on the costs of Screaming Cowbird parasitism on the Grayish Baywing’s reproductive success and how these costs have favored reciprocal adaptations and counter-adaptations at each stage of the nesting cycle.

Cytochrome P450 2D6 profiles and their relationship with outcomes of primaquine anti-relapse therapy in Australian Defence Force personnel deployed to Papua New Guinea and East Timor

BackgroundPrimaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated.MethodsGenomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999–2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3–5 (n = 9) relapses within the ADF-R group.Results16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group.ConclusionsCYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.

The brood parasite's guide to inclusive fitness theory.

Hamilton's theory of inclusive fitness provides a framework for understanding the evolution of social behaviour between kin, including parental and alloparental care. Brood parasitism is a reproductive tactic in which parasites exploit the care of other individuals of the same species (conspecific parasitism) or different species (interspecific parasitism) to rear their brood. Here, drawing from examples in birds and social insects, we identify two insights into brood parasitism that stem from inclusive fitness theory. First, the kin structure within nests, or between neighbouring nests, can create a niche space favouring the evolution of conspecific parasitism. For example, low average relatedness within social insect nests can increase selection for reproductive cheats. Likewise, high average relatedness between adjacent nests of some birds can increase a female's tolerance of parasitism by her neighbour. Second, intrabrood conflict will be high in parasitized broods, from the perspective of both parasite and host young, relative to unparasitized broods. We also discuss offspring recognition by hosts as an example of discrimination in a kin-selected social behaviour. We conclude that the inclusive fitness framework is instructive for understanding aspects of brood parasite and host evolution. In turn, brood parasites present some unique opportunities to test the predictions of inclusive fitness theory. This article is part of the theme issue 'The coevolutionary biology of brood parasitism: from mechanism to pattern'.

On the Design of <inline-formula> <tex-math notation="LaTeX">$n$ </tex-math> </inline-formula>th-Order Polyphase All-Pass Filters

A structure for $n$ th-order polyphase all-pass filters (PAFs) is proposed that improves the tradeoff between output phase accuracy and filter loss. The filter also has a well-defined input impedance, which is independent of the phase accuracy and can generate the exact desired phase at $n$ distinct frequencies. The proposed structure along with its design approach is analyzed. The design procedure to design a second, third, and fourth-order PAFs is presented. It is shown that by increasing the order of the PAF structure, one can either improve the phase accuracy of the structure over the same bandwidth of interest or achieve the same phase accuracy over a wider bandwidth. Practical design considerations, including the effect of the parasitic capacitances, component tolerance, and inductor quality factors on the output amplitude imbalance and input impedance, are analyzed and discussed. As a proof-of-concept, experimental results are presented to show that the fourth-order structure is able to generate quadrature signals at four distinct frequencies.

Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites.

In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.

Parasite Tolerance and Host Competence in Avian Host Defense to West Nile Virus.

Competence, or the propensity of a host to transmit parasites, is partly underlain by host strategies to cope with infection (e.g., resistance and tolerance). Resistance represents the ability of hosts to prevent or clear infections, whereas tolerance captures the ability of individuals to cope with a given parasite burden. Here, we investigated (1) whether one easy-to-measure form of tolerance described well the dynamic relationships between host health and parasite burden, and (2) whether individual resistance and tolerance to West Nile virus (WNV) were predictable from single cytokine measures. We exposed house sparrows (HOSP) to WNV and measured subsequent changes in host performance, viral burden, and cytokine expression. We then used two novel approaches (one complex, one simpler) to estimate tolerance within-individual HOSP using four separate host performance traits. We lastly investigated changes in the expression of pro-inflammatory cytokine interferon-γ (IFN-γ) and anti-inflammatory cytokine interleukin-10 (IL-10). Both approaches to estimating tolerance were equivalent among WNV-infected HOSP; thus, an easy-to-measure tolerance estimation may be successfully applied in field studies. Constitutive expression of IFN-γ and IL-10 were predictive of resistance and tolerance to WNV, implicating these cytokines as viable biomarkers of host competence to WNV.

Barbados Blackbelly: the Caribbean ovine genetic resource.

Ovine production is one of the most important activities in animal production in tropical regions. The Barbados Blackbelly, a very interesting genetic resource, particularly well adapted to a harsh home environment in the humid tropics of the Caribbean. This review concerns this breed. It comprises aspects related to the breed history and standards and most importantly its reproductive and productive performances and gastrointestinal parasite tolerance in the Caribbean, North America and Central America and their introduction and use in crossbred trials in other regions of the tropics.