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Epigenetic modifications play important roles in the biology of malaria parasites. The new epigenetic mark histone lactylation, discovered only recently in humans, is also present in malaria parasites. It may have important functions as a key player in the epigenetic repertoire of Plasmodium.

The ability of the intraerythrocytic Plasmodium spp. to form spontaneous rosettes with uninfected red blood cells (URBCs) has been observed in the medically important malaria parasites. Since the discovery of rosettes in the late 1980s, different formation mechanisms and pathobiological roles have been postulated for rosetting; most of which have focused on Plasmodium falciparum. Recent breakthroughs, including new data from Plasmodium vivax, have highlighted the multifaceted roles of rosetting in the immunopathobiology and the development of drug resistance in human malaria. Here, we provide new perspectives on the formation and the role of rosetting in malaria rheopathobiology.

The ambitious goal of malaria elimination requires an in-depth understanding of the parasite's biology to counter the growing threat of antimalarial resistance and immune evasion. Timely assessment of the functional impact of antigenic diversity in the early stages of vaccine development will be critical for achieving the goal of malaria control, elimination, and ultimately eradication. Recent advances in targeted genome editing enabled the functional validation of resistance-associated markers in Plasmodium falciparum, the deadliest malaria-causing pathogen and strain-specific immune neutralization. This review explores recent advances made in leveraging genome editing to aid the functional evaluation of Plasmodium diversity and highlights how these techniques can assist in prioritizing both therapeutic and vaccine candidates.

Complications from placental malaria cause poor pregnancy outcomes, including low birthweight, preterm delivery, and stillbirths. Many of these complications are driven by maternal innate proinflammatory responses to the sequestration of Plasmodium falciparum in the placenta. However, recent studies show that, in reaction to maternal innate immune responses that are detrimental to the fetus, the fetus mounts innate immune counter-responses that ameliorate pregnancy outcomes. Such fetal-maternal conflict in placental malaria has potential for pharmacologic modulation for better pregnancy outcomes. Here, we discuss placental malaria pathogenesis, its complications, and the role of innate immunity and fetal-maternal innate immune conflict in placental malaria. Finally, we discuss pharmacologic immunomodulatory strategies and agents with the potential to improve placental malaria outcomes.

IgG antibodies are key effector molecules in acquired immunity to Plasmodium falciparum malaria, and the PfEMP1 adhesins expressed on the surface of the infected erythrocytes are crucial immunological targets. The antigen specificity of these antibodies has therefore been a major research focus. However, we recently reported that the Fc domain of naturally induced PfEMP1-specific IgG1 is selectively modified by post-translational omission of fucose from the conserved Fc glycan. The resulting afucosylated IgG has increased affinity for the IgG-Fc-receptor III family (FcγRIII), found on natural killer cells and on subsets of other cells in the immune system. We discuss the implications of these findings for the basic understanding of antimalarial immunity and for the design of improved vaccines against the disease.

Recent progress in genomics and molecular genetics has empowered novel approaches to closely study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, the application of genome-based analyses, site-directed genome editing, and genetic systems that allow for temporal and quantitative regulation of gene and protein expression have been invaluable in defining the genetic basis of antimalarial resistance and elucidating candidate targets to accelerate drug discovery efforts. Using examples from recent studies, we review applications of some of these approaches in advancing our understanding of Plasmodium biology and illustrate their contributions and limitations in characterizing parasite genomic loci associated with antimalarial drug responses.

Plasmodium falciparum pathogenesis is complex and intimately connected to vascular physiology. This is exemplified by cerebral malaria (CM), a neurovascular complication that accounts for most of the malaria deaths worldwide. P. falciparum sequestration in the brain microvasculature is a hallmark of CM and is not replicated in animal models. Numerous aspects of the disease are challenging to fully understand from clinical studies, such as parasite binding tropism or causal pathways in blood-brain barrier breakdown. Recent bioengineering approaches allow for the generation of 3D microvessels and organ-specific vasculature that provide precise control of vessel architecture and flow dynamics, and hold great promise for malaria research. Here, we discuss recent and future applications of bioengineered microvessels in malaria pathogenesis research.

Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria - Plasmodium falciparum. We reveal developmental trajectories associated with the colonization of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and non-conserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, provide a fine-grained atlas that enables intensive investigation of the P. falciparum transcriptional journey. As well as providing insights into gene function across the transmission cycle, the atlas opens the door for identification of drug and vaccine targets to stop malaria transmission and thereby prevent disease.

Recent gains in the fight against malaria are threatened by the emergence and spread of artemisinin and partner drug resistance in Plasmodium falciparum in the Greater Mekong Subregion (GMS). When artemisinins are combined with a single partner drug, all recommended artemisinin-based combination therapies have shown reduced efficacy in some countries in the GMS at some point. Novel drugs are not available for the near future. Triple artemisinin-based combination therapies, combining artemisinins with two currently available partner drugs, will provide one of the last remaining safe and effective treatments for falciparum malaria that can be deployed rapidly in the GMS, whereas their deployment beyond the GMS could delay or prevent the global emergence and spread of resistance to currently available drugs.

Contains fulltext : 229558.pdf (Publisher’s version ) (Closed access) Malaria eradication is a global priority but requires innovative strategies. Humoral immune responses attack different parasite stages, and antibody-based therapy may prevent malaria infection or transmission. Here, we discuss targets of monoclonal antibodies in mosquito sexual stages of Plasmodium.

The Plasmodium liver stage represents a vulnerable therapeutic target to prevent disease progression as the parasite resides in the liver before clinical representation caused by intraerythrocytic development. However, most antimalarial drugs target the blood stage of the parasite's life cycle, and the few drugs that target the liver stage are lethal to patients with a glucose-6-phosphate dehydrogenase deficiency. Furthermore, implementation of in vitro liver models to study and develop novel therapeutics against the liver stage of human Plasmodium species remains challenging. In this review, we focus on the progression of in vitro liver models developed for human Plasmodium spp. parasites, provide a brief review on important assay requirements, and lastly present recommendations to improve models to enhance the discovery process of novel preclinical therapeutics.

The first experimental crosses carried out with the human malaria parasite Plasmodium falciparum played a key role in determining the genetic loci responsible for drug resistance, virulence, invasion, growth rate, and transmission. These crosses relied on splenectomized chimpanzees to complete the liver stage of the parasite's life cycle and the subsequent transition to asexual blood stage culture followed by cloning of recombinant progeny in vitro. Crosses can now be routinely carried out using human-liver-chimeric mice infused with human erythrocytes to generate hundreds of unique recombinant progeny for genetic linkage mapping, bulk segregant analysis, and high-throughput 'omics readouts. The high number of recombinant progeny should allow for unprecedented power and efficiency in the execution of a systems genetics approach to study P. falciparum biology.

Plasmodium vivax is an important cause of malaria, associated with a significant public health burden. Whilst enhanced malaria-control activities have successfully reduced the incidence of Plasmodium falciparum malaria in many areas, there has been a consistent increase in the proportion of malaria due to P. vivax in regions where both parasites coexist. This article reviews the epidemiology and biology of P. vivax, how the parasite differs from P. falciparum, and the key features that render it more difficult to control and eliminate. Since transmission of the parasite is driven largely by relapses from dormant liver stages, its timely elimination will require widespread access to safe and effective radical cure.

Experimental research into malaria biology and pathogenesis has historically focused on two model systems, in vitro culture of the human parasite Plasmodium falciparum and in vivo infections of laboratory animals using rodent parasites. While there is clear value in having a manipulatable animal model for studying malaria, there have occasionally been controversies around how representative the rodent model is of the human disease, and therefore significant emphasis has been placed on the similarities between the two biological systems. By focusing on basic nuclear functions, we wish to highlight that identifying key differences in the parasites and their interactions with their mammalian hosts can be equally informative and provide remarkable insights into the biology and evolution of these important infectious organisms.

Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.

Despite ongoing efforts, a highly effective vaccine against Plasmodium falciparum remains elusive. Vaccines targeting the pre-erythrocytic stages of the P. falciparum life cycle are the most advanced to date, affording moderate levels of efficacy in field trials. However, the discovery that the members of the merozoite PfRH5-PfCyRPA-PfRipr (RCR) complex are capable of inducing strain-transcendent neutralizing antibodies has renewed enthusiasm for the possibility of preventing disease by targeting the parasite during the blood stage of infection. With Phase I/II clinical trials now underway using first-generation vaccines against PfRH5, and more on the horizon for PfCyRPA and PfRipr, this review explores the rationale and future potential of the RCR complex as a P. falciparum vaccine target., Highlights The antigens PfRH5, PfCyRPA, and PfRipr can induce strain-transcendent neutralizing antibodies, and all three targets are essential and highly conserved. PfRH5, PfCyRPA, and PfRipr form a stable complex (RCR) that is involved in the induction of an erythrocytic calcium spike during merozoite invasion. Passive transfer of anti-CyRPA and anti-PfRH5 antibodies can protect against blood-stage P. falciparum in animal models. Structural studies have mapped out the first known critical inhibitory epitopes on PfRH5 and PfCyRPA which can be used for next-generation vaccine design. Early results from the first PfRH5 vaccine clinical trials have been reported with more anticipated soon, which will help guide the development of RCR-based vaccines.

A large body of evidence demonstrates that Plasmodium falciparum infections are chronic in malaria endemic areas; however, the notion of spontaneous clearance in the absence of antimalarial drug treatment is rarely discussed. In this opinion article, we review and reinterpret data to postulate that spontaneous clearance of P. falciparum infections occurs frequently, has been demonstrated in a range of transmission settings, and confirmed by the most sensitive malaria diagnostic techniques. We also discuss factors which may influence the likelihood, measurement, and conclusions of spontaneous clearance. A greater understanding of the phenomenon of spontaneous clearance will advance our knowledge of malaria epidemiology, transmission potential of malaria parasites, as well as inform interventions for malaria control and elimination.

Preventing human-to-mosquito transmission of malaria parasites provides possible solutions to interrupt the malaria parasite life cycle for malaria elimination. The development of validated routine assays enabled the discovery of such transmission-blocking compounds. Currently, one development priority remains on combinations of dual-active compounds with equipotent activity against both the disease-causing asexual and transmissible, sexual erythrocytic stages. Additionally, transmission-blocking compounds that target gametocyte-specific biology could be used in combination with compounds against asexual parasites. In either case, preventing transmission will reduce the risk of reinfection and, if different processes are targeted, also curb the spread of drug resistance. Here, we provide an updated roadmap to the discovery and development of new antimalarials with transmission-blocking activity to guide drug discovery for malaria elimination.

A critical step in malaria blood-stage infections is the invasion of red blood cells (RBCs) by merozoite forms of the Plasmodium parasite. Much progress has been made in defining the parasite ligands and host receptors that mediate this critical step. However, less well understood are the RBC biophysical determinants that influence parasite invasion. In this review we explore how Plasmodium falciparum merozoites interact with the RBC membrane during invasion to modulate RBC deformability and facilitate invasion. We further highlight RBC biomechanics-related polymorphisms that might have been selected for in human populations due to their ability to reduce parasite invasion. Such an understanding will reveal the translational potential of targeting host pathways affecting RBC biomechanical properties for the treatment of malaria.

In the early 2000s, artemisinin-based combination therapy (ACT) was introduced as first-line treatment for uncomplicated Plasmodium falciparum malaria in virtually all endemic countries. However, despite the well-known excellent tolerability of ACTs, hypersensitivity to artemisinin derivatives remains a repeatedly documented adverse drug reaction of still unknown frequency. The clinical features of an artemisinin-induced hypersensitivity reaction range from mild to life-threatening severity, and a significant number of cases may pass unnoticed. In this review, we discuss the medical importance of hypersensitivity to artemisinin derivatives and we review data on the presumed frequency and its potential underlying mechanisms. Furthermore, we advocate to make alternative non-artemisinin-based drugs available for patients who do not tolerate artemisinin derivatives and to continue investing in the development of novel non-artemisinin-based combination regimens.

Women attending antenatal care (ANC) are a generally healthy, easy-access population, contributing valuable data for infectious disease surveillance at the community level. ANC-based malaria surveillance would provide a routine measure of the malaria burden in pregnancy, which countries lack, whilst potentially improving pregnancy outcomes. It could also offer contemporary information on temporal trends and the geographic distribution of malaria burden as well as intervention coverage in the population to guide resource allocation and to assess progress towards elimination. Here, we review the factors underlying the relationship between Plasmodium falciparum in pregnancy and in the community, and outline strengths and limitations of an ANC-based surveillance in sub-Saharan Africa, its potential role within wider malaria surveillance systems, and subsequent programmatic applications.

Population genomics of bulk malaria infections is unable to examine intrahost evolution, so most work has focused on the role of recombination in generating genetic variation. We used single cell sequencing protocol for low parasitemia infections to generate 406 near complete single Plasmodium vivax genomes from 11 patients sampled during sequential febrile episodes. Parasite genomes contained hundreds of de novo mutations, showing strong signatures of selection, which are enriched in the ApiAP2 family of transcription factors, known targets of adaptation. Comparing 315 P. falciparum single cell genomes from 15 patients with our P. vivax data we find broad complementary patterns of de novo mutation at the gene and pathway level, revealing the importance of within host evolution during malaria infections.

Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compounds would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compounds as early as possible in preclinical development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clinical failure for candidate therapeutics, and inform decisions to guide antimalarial drug development.

The Plasmodium falciparum protein VAR2CSA is a critical mediator of placental malaria, and VAR2CSA antibodies (IgGs) are important to protect pregnant women. Although infrequently detected outside pregnancy, VAR2CSA IgGs were reported in men and children from Colombia and Brazil and in select African populations. These findings raise questions about the specificity of VAR2CSA IgGs and the mechanisms by which they are acquired outside pregnancy. Here we review the data on VAR2CSA IgGs in men and children from different malaria-endemic regions. We discuss experimental factors that may affect interpretation of the serological data and consider the biological relevance of VAR2CSA IgGs in non-pregnant populations. We propose potential mechanisms for the acquisition of VARCSA IgGs outside of pregnancy. We identify knowledge gaps and research priorities.

© 2018 Elsevier Ltd Molecular surveillance of antimalarial drug resistance markers has become an important part of resistance detection and containment. In the current climate of multidrug resistance, including resistance to the global front-line drug artemisinin, there is a consensus to upscale molecular surveillance. The most salient limitation to current surveillance efforts is that skill and infrastructure requirements preclude many regions. This includes sub-Saharan Africa, where Plasmodium falciparum is responsible for most of the global malaria disease burden. New molecular and data technologies have emerged with an emphasis on accessibility. These may allow surveillance to be conducted in broad settings where it is most needed, including at the primary healthcare level in endemic countries, and extending to the village health worker.

Malaria prevalence has declined in the past 10 years, especially outside of sub-Saharan Africa. However, the proportion of cases due to Plasmodium vivax is increasing, accounting for up to 90-100% of the malaria burden in endemic regions. Nonetheless, investments in malaria research and control still prioritize Plasmodium falciparum while largely neglecting P. vivax. Specific biological features of P. vivax, particularly invasion of reticulocytes, occurrence of dormant liver forms of the parasite, and the potential for transmission of sexual-stage parasites prior to onset of clinical illness, promote its persistence and hinder development of research tools and interventions. This review discusses recent advances in P. vivax research, current knowledge of its unique biology, and proposes priorities for P. vivax research and control efforts.

The majority of malaria parasites during human infection are asexual and are unable to be transmitted to mosquitoes. Only sexually differentiated parasites (gametocytes) can be successfully transmitted to complete the lifecycle. In a recent study by Bancells et al. (Nat. Microbiol. 2019;4:144–154), a new route of sexual conversion is identified that does not require a prior round of replication.

Artemisinin (ART)-based combination therapies are the most efficacious treatment of uncomplicated Plasmodium falciparum malaria. Alarmingly, P. falciparum strains have acquired resistance to ART across much of Southeast Asia. ART creates widespread protein and lipid damage inside intraerythrocytic parasites, necessitating macromolecule degradation. The proteasome is the main engine of Plasmodium protein degradation. Indeed, proteasome inhibition and ART have shown synergy in ART-resistant parasites. Moreover, ubiquitin modification is associated with altered parasite susceptibility to multiple antimalarials. Targeting the ubiquitin-proteasome system (UPS), therefore, is an attractive avenue to combat drug resistance. Here, we review recent advances leading to specific targeting of the Plasmodium proteasome. We also highlight the potential for targeting other nonproteasomal protein degradation systems as an additional strategy to disrupt protein homeostasis.

International audience; Preventing malaria infection through vaccination requires preventing every sporozoite inoculated by mosquito bite: a major challenge for Plasmodium falciparum. Plasmodium vivax sporozoites consist of tachysporozoites causing primary infection and bradysporozoites leading to relapses. We hypothesise that a candidate P. vivax vaccine with low efficacy against primary infection may substantially reduce transmission by preventing relapses.

Severe malaria due to Plasmodium falciparum infection causes nearly half a million deaths per year. The different symptomatology and disease manifestations among patients have hampered understanding of severe malaria pathology and complicated efforts to develop targeted disease interventions. Infected erythrocyte sequestration in the microvasculature plays a critical role in the development of severe disease, and there is increasing evidence that cytoadherent parasites interact with host factors to enhance the damage caused by the parasite. The recent discovery that parasite binding to endothelial protein C receptor (EPCR) is associated with severe disease has suggested new mechanisms of pathology and provided new avenues for severe malaria adjunctive therapy research.

Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination., Trends Antimalarial drugs are being used in many different contexts beyond treatment of disease – increasingly with the aim of reducing malaria transmission in a community. Each drug has different attributes – killing efficacy against asexual parasites, duration of effect, gametocytocidal activity, mosquitocidal activity, liver-stage activity (for Plasmodium vivax), dosing schedule and toxicity. Drug attributes need to be rationally combined to match their usage aims based on a quantitative understanding of their properties. For transmission reductions, the individual patient approach is less relevant and a population-level perspective is critical. Rational approaches to combining drugs with other forms of malaria control to reduce malaria transmission can only be made using transmission models informed by field data, given the difficulty of testing all combinations of interventions in all settings.

International audience; Malarial infections have long been recognized as a driver of human evolution, as demonstrated by the influence of Plasmodium falciparum on sickle-cell anemia persistence. Duffy-negativity is another blood disorder thought to have been selected because it confers nearly complete resistance against Plasmodium vivax infection. Recent evidence suggests that the benefits of being Duffy-negative cannot be expected to play a strong selective pressure on humans, whereas its costs cannot be considered as negligible. Here, we suggest that the cross-talk between P. falciparum and P. vivax in coinfected children could represent the most parsimonious explanation of the frequency of Duffy-negativity. We discuss how this new hypothesis could be tested and call for a reconsideration of the evolution of the Duffy-negative group.

Summary The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria., Graphical Abstract, Highlights • Human PfRH5 vaccination induces cross-reactive neutralizing antimalarial antibodies • Neutralizing human PfRH5 antibodies bind epitopes close to the basigin binding site • Some non-neutralizing antibodies potentiate those binding several malaria proteins • Potentiating antibodies slow erythrocyte invasion by binding a new epitope on PfRH5, Analyses of human monoclonal antibodies against the Plasmodium falciparum protein PfRH5 identify a subset of non-neutralizing antibodies that synergize with a repertoire of other neutralizing antibodies by slowing the ability of malaria-causing parasites to invade red blood cells.

Malaria parasites possess the remarkable ability to maintain chronic infections that fail to elicit a protective immune response, characteristics that have stymied vaccine development and cause people living in endemic regions to remain at risk of malaria despite previous exposure to the disease. These traits stem from the tremendous antigenic diversity displayed by parasites circulating in the field. For Plasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family called var, which encodes the major surface antigen displayed on infected red blood cells (RBCs). This gene family exhibits virtually limitless diversity when var gene repertoires from different parasite isolates are compared. Previous studies indicated that this remarkable genome plasticity results from extensive ectopic recombination between var genes during mitotic replication; however, the molecular mechanisms that direct this process to antigen-encoding loci while the rest of the genome remains relatively stable were not determined. Using targeted DNA double-strand breaks (DSBs) and long-read whole-genome sequencing, we show that a single break within an antigen-encoding region of the genome can result in a cascade of recombination events leading to the generation of multiple chimeric var genes, a process that can greatly accelerate the generation of diversity within this family. We also found that recombinations did not occur randomly, but rather high-probability, specific recombination products were observed repeatedly. These results provide a molecular basis for previously described structured rearrangements that drive diversification of this highly polymorphic gene family., Malaria parasites have a remarkable capacity to continuously generate genetically diverse surface antigens, helping them to evade the host immune response. This study reveals the unusual recombination mechanism which accelerates the diversification of this gene family in Plasmodium falciparum, the most severe of the human malarial parasites.

Cerebral malaria is a life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The growing problem of drug resistance and the dearth of new antiparasitic drugs are a serious threat to the antimalaria treatment regimes. Studies on humans and the murine model have implicated the disruption of the blood–brain barrier (BBB) in the lethal course of the disease. Therefore, efforts to alleviate the BBB dysfunction could serve as an adjunct therapy. Here, we review the mechanisms associated with the disruption of the BBB. In addition, we discuss the current, still limited, knowledge on the contribution of different cell types, microparticles, and the kynurenine pathway in the regulation of BBB dysfunction, and how these molecules could be used as potential new therapeutic targets.

Phenotypic high throughput screens are a valuable tool for identifying new chemical compounds with antimalarial activity. Traditionally, these screens have focused solely on the symptomatic asexual blood stage of the parasite's lifecycle; however, in order to discover new medicines for malaria's treatment and prevention, robust screening technologies against other parasite lifecycle stages are required. This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens.

Erythrocyte invasion by Plasmodium falciparum merozoites is an essential step for parasite survival and proliferation. Invasion is mediated by multiple ligands, which could be promising vaccine targets. The usage and sequence of these ligands differs between parasites, yet most studies of them have been carried out in only a few laboratory-adapted lines. To understand the true extent of natural variation in invasion phenotypes and prioritize vaccine candidates on a relevant evidence base, we need to develop and apply standardized assays to large numbers of field isolates. The West African Merozoite Invasion Network (WAMIN) has been formed to meet these goals, expand training in Plasmodium phenotyping, and perform large-scale field phenotyping studies in order to prioritize blood stage vaccine candidates.

Malaria vaccine development is hampered by the lack of small animal models that recapitulate human immune responses to Plasmodium falciparum. We review the burgeoning literature on humanized mice for P. falciparum infection, including challenges in engraftment of human immune cells, hepatocytes, and erythrocytes. Recent advances in immune-compromised mouse models and stem cell technology have already enabled proof of concept that the entire parasite life cycle can be sustained in a murine model and that adaptive human immune responses to several parasite stages can be measured. Nonetheless, optimization is needed to achieve a reproducible and relevant murine model for malaria vaccine development. This review is focused on the complexities of T cell development in a mouse humanized with both a lymphoid system and hepatocytes. An understanding of this will facilitate the use of humanized mice in the development of liver-stage vaccines.

The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.

Contains fulltext : 203071.pdf (Publisher’s version ) (Closed access) Plasmodium gametocytes can induce an immune response in humans that interferes with the development of sexual-stage parasites in the mosquito gut. Many early studies of the sexual-stage immune response noted that mosquito infection could be enhanced as well as reduced by immune sera. For Plasmodium falciparum, these reports are scarce, and the phenomenon is generally regarded as a methodological artefact. Plasmodium transmission enhancement (TE) remains contentious, but the clinical development of transmission-blocking vaccines based on sexual-stage antigens requires that it is further studied. In this essay, we review the early literature on the sexual-stage immune response and transmission-modulating immunity. We discuss hypotheses for the mechanism of TE, suggest experiments to prove or disprove its existence, and discuss its possible implications.

In vector-borne disease systems, there is mounting evidence that vertebrate hosts become more attractive to disease vectors during infection, yet in human malaria, the underlying mechanism has not been studied. We identified compounds, including aldehydes, that are produced in relatively greater amounts in the skin odor of individuals with malaria, thus demonstrating a basis for this phenomenon in the cues used during mosquito host location. By establishing the attractiveness of these compounds to malaria mosquito vectors in laboratory bioassays, we characterize a process by which Plasmodium infection of humans could lead to increased mosquito biting. These compounds may serve as biomarkers of malaria or be used to enhance the efficacy of chemical lures used to trap mosquitoes.

Renewed interest in malaria eradication has placed greater emphasis on the development of tools to interrupt Plasmodium transmission, such as transmission-blocking vaccines. However, effective deployment of such tools is likely to depend on improving our understanding of which individuals transmit infections to mosquitoes. To date, only a handful of studies have directly determined the infectiousness of individuals in endemic populations. Here we review these studies and their relative merits. We also highlight factors influencing transmission potential that are not normally considered: the duration of human infectiousness, frequency of sampling by mosquitoes, and variation in vector competence among different mosquito populations. We argue that more comprehensive xenodiagnostic assessments of infectivity are necessary to accurately quantify the infectious reservoir and better target interventions.

Item does not contain fulltext The spread of malaria critically relies on the presence of Plasmodium transmission stages - the gametocytes - circulating in the blood of an infected individual, which are taken up by Anopheles mosquitoes. A striking feature of Plasmodium falciparum gametocytes is their long development inside the erythrocytes while sequestered in the internal organs of the human host. Recent studies of the molecular and cellular remodeling of the host erythrocyte induced by P. falciparum during gametocyte maturation are shedding light on how these may affect the establishment and maintenance of sequestration of the immature transmission stages and the subsequent release and circulation of mature gametocytes in the peripheral bloodstream.

Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps have rendered sulfadoxine-pyrimethamine (SP) ineffective for malaria treatment in most regions of the world. Yet, SP is efficacious as intermittent preventive therapy in pregnant women (IPTp) and infants (IPTi) and as seasonal malaria control in children (SMC). SP-IPTp is being widely implemented in sub-Saharan Africa. SP-IPTi is recommended where the prevalence of SP-resistant malaria parasites is low, whereas SMC is recommended for areas of intense seasonal malaria transmission. The continuing success of these interventions depends largely on the prevalence of Pfdhfr and Pfdhps resistance mutations in the target population. Here we review the relationship between resistance mutations and SP-IPT within target populations in the context of monitoring and informing implementation of this intervention.

Item does not contain fulltext Epidemiological studies have demonstrated an association between malaria and invasive non-typhoid Salmonella (NTS) infections, especially in children. We explore the role of iron as a possible cofactor in this association. Malarial disease, among others, is associated with enhanced erythrophagocytosis and inflammation, which increases the iron content of macrophages and thereby also the survival of Salmonella spp. within macrophages. Whether iron supplementation programs augment the risk of invasive NTS infections in malaria-endemic regions is an important global health issue that still needs to be determined.

Blood stage malaria parasites target a ’secretome’ of hundreds of proteins including virulence determinants containing a host (cell) targeting (HT) signal, to human erythrocytes. Recent studies reveal that the export mechanism is due to the HT signal binding to the lipid phosphatidylinositol-3-phosphate (PI(3)P) in the parasite endoplasmic reticulum (ER). An aspartic protease plasmepsin V which cleaves a specialized form of the HT signal was previously thought to be the export mechanism, but is now recognized as a dedicated peptidase that cleaves the signal anchor subsequent to PI(3)P binding. We discuss a model of PI(3)P-dependent targeting and PI(3)P biology of a major human pathogen.

It is becoming increasingly evident that epigenetic mechanisms that act on and regulate chromatin structure play a key role in the development, adaptation, and survival of the malaria parasite within its human host. The study of epigenetics in Plasmodium falciparum started to flourish in recent years due to improvement of genomic technologies. Here we summarize the knowledge gained from genome-wide localization profiling of different epigenetic features, and discuss hypotheses emerging from the analysis of these 'descriptive' epigenetic maps. Furthermore, we highlight key questions to be answered, and provide a glimpse of developments required to gain true mechanistic understanding and to lift this maturing field to the next level.

Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the ‘Chloroquine Resistance Transporter’ (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes.