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In the last 10 years, proximity-dependent biotinylation (PDB) techniques greatly expanded the ability to study protein environments in the living cell that range from specific protein complexes to entire compartments. This is achieved by using enzymes such as BirA* and APEX that are fused to proteins of interest and biotinylate proteins in their proximity. PDB techniques are now also increasingly used in apicomplexan parasites. In this review, we first give an overview of the main PDB approaches and how they compare with other techniques that address similar questions. PDB is particularly valuable to detect weak or transient protein associations under physiological conditions and to study cellular structures that are difficult to purify or have a poorly understood protein composition. We also highlight new developments such as novel smaller or faster-acting enzyme variants and conditional PDB approaches, providing improvements in both temporal and spatial resolution which may offer broader application possibilities useful in apicomplexan research. In the second part, we review work using PDB techniques in apicomplexan parasites and how this expanded our knowledge about these medically important parasites., (© 2021 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Most asexual vivax parasites accumulate in the reticulocyte-rich spleen, replicating in an endosplenic life cycle. This reservoir contributes to systemic inflammation and anemia, and helps maintain chronic infections and transmission. Plasmodium vivax merozoites preferentially invade nascent reticulocytes over mature reticulocytes through newly identified invasion pathways. Humanized mice and hepatocyte culture systems are characterizing hypnozoite biology, and new approaches for anti-relapse therapy. Anemia is mostly from splenic retention of uninfected red cells; frequently recurring and chronic infections cause progressive anemia, malnutrition, and death, especially in young children. Endothelial cell activation, a predictor of impaired perfusion and death in falciparum malaria, is even more pronounced in acute vivax malaria, likely contributing to organ dysfunction in severe disease. Plasmodium vivax contributes significantly to global malaria morbidity. Key advances include the discovery of pathways facilitating invasion by P. vivax merozoites of nascent reticulocytes, crucial for vaccine development. Humanized mouse models and hepatocyte culture systems have enhanced understanding of hypnozoite biology. The spleen has emerged as a major reservoir for asexual vivax parasites, replicating in an endosplenic life cycle, and contributing to recurrent and chronic infections, systemic inflammation, and anemia. Splenic accumulation of uninfected red cells is the predominant cause of anemia. Recurring and chronic infections cause progressive anemia, malnutrition, and death in young children in high-transmission regions. Endothelial activation likely contributes to vivax-associated organ dysfunction. The many recent advances in vivax pathobiology should help guide new approaches to prevention and management. [ABSTRACT FROM AUTHOR]

Background: Reducing mosquito abundance or interfering with its ability to support the parasite cycle can help to interrupt malaria in areas of significant risk of malaria transmission. Fluralaner is a safe and effective drug for veterinary use indicated for the treatment against fleas and ticks which acts as an antagonist of chloride ion channels mediated by γ-aminobutyric acid (GABA), preventing the entry of these ions into the postsynaptic neuron, leading to hyperexcitability of the postsynaptic neuron of the central nervous system of arthropods. Fluralaner demonstrated insecticidal activity against different insect species. Methods: The study aimed to evaluate the effects of fluralaner on the biology, survival, and reproductive fitness of Anopheles aquasalis. The following lethal concentrations (LC) were determined for An. aquasalis: LC5 = 0.511 µM; LC25 = 1.625 µM; LC50 = 3.237 µM. Results: A significant decrease (P < 0.001) was evident in the number of eggs, larvae, and pupae in the group exposed to a sublethal dose of fluralaner when compared to a control group (without the drug). Using blood from dogs after administration of fluralaner, it was observed that the drug causes 100% mortality in An. aquasalis in less than 24 h after feeding; this effect remains even after 90 days in all samples. Discussion: Fluralaner showed the same result for up to 60 days, and after that, there was a slight reduction in its effect, evidenced by a decrease in the percentage of dead females; however, still significant when compared to the control group. Conclusion: Fluralaner affects the biology and reduction of survival in An. aquasalis in a lasting and prolonged period, and its fecundity with lower dosages, is a strong candidate for controlling disease vectors. [ABSTRACT FROM AUTHOR]

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Plasmodium cynomolgi (Pcy), a simian malaria parasite, is a recent perfect example of emerging zoonotic transfer in human. This review summarizes the current knowledge on the epidemiology of natural Pcy infections in humans, mosquitoes and monkeys, along with its biological, clinical and drug sensitivity patterns. Knowledge gaps and further studies on Pcy in humans are also discussed. This parasite currently seems to be geographically limited in South-East Asia (SEA) with a global prevalence in human ranging from 0 to 1.4%. The Pcy infections were reported in local SEA populations and European travelers, and range from asymptomatic carriage to mild/moderate attacks with no evidence of pathognomonic clinical and laboratory patterns but with Pcy strain-shaped clinical differences. Geographical distribution and competence of suitable mosquito vectors and non-primate hosts, globalization, climate change, and increased intrusion of humans into the habitat of monkeys are key determinants to emergence of Pcy parasites in humans, along with its expansion outside SEA. Sensitization/information campaigns coupled with training and assessment sessions of microscopists and clinicians on Pcy are greatly needed to improve data on the epidemiology and management of human Pcy infection. There is a need for development of sensitive and specific molecular tools for individual diagnosis and epidemiological studies. The development of safe and efficient anti-hypnozoite drugs is the main therapeutic challenge for controlling human relapsing malaria parasites. Experience gained from P. knowlesi malaria, development of integrated measures and strategies—ideally with components related to human, monkeys, mosquito vectors, and environment—could be very helpful to prevent emergence of Pcy malaria in humans through disruption of transmission chain from monkeys to humans and ultimately contain its expansion in SEA and potential outbreaks in a context of malaria elimination. [ABSTRACT FROM AUTHOR]

The long term in vitro culture of Plasmodium falciparum was successfully established by Trager and Jensen in 1976; however it largely remains unachieved for P. vivax. The major obstacle associated with Plasmodium vivax in vitro culture is its predilection for invading younger reticulocytes and the complex remodelling of invaded reticulocytes. There are many factors under exploration for this predilection and host--parasite interactions between merozoites and invaded reticulocytes. These include various factors related to parasite, host and environment such as compromised reticulocyte osmotic stability after invasion, abundance of iron in the reticulocytes which makes them favourable for P. vivax growth and propagation and role of a hypoxic environment in P. vivax in vitro growth. P. vivax blood stage transfection represents another major hurdle towards understanding this parasite's complex biology. Efforts in making this parasite amenable for molecular investigation by genetic modification are limited. Newer approaches in sustaining a longer in vitro culture and thereby help advancing transfection technologies in P. vivax are urgently needed that can be explored to understand the unique biology of this parasite. [ABSTRACT FROM AUTHOR]

Genotyping Plasmodium vivax relapses can provide insights into hypnozoite biology. We performed targeted amplicon sequencing of 127 relapses occurring in Indonesian soldiers returning to malaria-free Java after yearlong deployment in malarious Eastern Indonesia. Hepatic carriage of multiple hypnozoite clones was evident in three-quarters of soldiers with two successive relapses, yet the majority of relapse episodes only displayed one clonal population. The number of clones detected in relapse episodes decreased over time and through successive relapses, especially in individuals who received hypnozoiticidal therapy. Interrogating the multiplicity of infection in this P. vivax relapse cohort reveals evidence of independent activation and slow depletion of hypnozoites over many months by multiple possible mechanisms, including parasite senescence and host immunity. Author summary: Investigating relapse patterns in infections of Plasmodium vivax, a parasite that causes malaria, is challenging due to concurrent reinfection events alongside true relapses in most clinical cohorts. We performed sequencing on P. vivax samples from a cohort of Indonesian soldiers who were exposed to the parasite while deployed in a malaria-endemic region and then experienced relapses after their return to a region with no current malaria transmission. From these true relapses, we show that most infected individuals harbor multiple lineages of hypnozoites (latent liver stage parasites that reactivate to cause relapse) but individual relapses are largely driven by a single hypnozoite lineage or clone. Additionally, the average number of parasite clones detected in each relapse decreases over time. These findings suggest that P. vivax hypnozoites activate independently from each other and that their population in the liver decreases over time after the initial infection, possibly due to immune clearance or loss of parasite viability. [ABSTRACT FROM AUTHOR]

Plasmodium parasites have a complex life cycle that includes development in the human host as well as the Anopheles vector. Successful transmission of the parasite between its host and vector therefore requires the parasite to balance its investments in asexual replication and sexual reproduction, varying the frequency of sexual commitment to persist within the human host and generate future opportunities for transmission. The transmission window is extended further by the ability of stage V gametocytes to circulate in peripheral blood for weeks, whereas immature stage I to IV gametocytes sequester in the bone marrow and spleen until final maturation. Due to the low gametocyte numbers in blood circulation and with the ease of targeting such life cycle bottlenecks, transmission represents an efficient target for therapeutic intervention. The biological process of Plasmodium transmission is a multistage, multifaceted process and the past decade has seen a much deeper understanding of the molecular mechanisms and regulators involved. Clearly, specific and divergent processes are used during transmission compared to asexual proliferation, which both poses challenges but also opportunities for discovery of transmission-blocking antimalarials. This review therefore presents an update of our molecular understanding of gametocyte and gamete biology as well as the status of transmission-blocking activities of current antimalarials and lead development compounds. By defining the biological components associated with transmission, considerations for the development of new transmission-blocking drugs to target such untapped but unique biology is suggested as an important, main driver for transmission-blocking drug discovery. [ABSTRACT FROM AUTHOR]

Malaria remains a vector-borne infectious disease that is still a major public health concern worldwide, especially in tropical regions. Malaria is caused by a protozoan parasite of the genus Plasmodium and transmitted through the bite of infected female Anopheles mosquitoes. The control interventions targeting mosquito vectors have achieved significant success during the last two decades and rely mainly on the use of chemical insecticides through the insecticide-treated nets (ITNs) and indoor residual spraying (IRS). Unfortunately, resistance to conventional insecticides currently being used in public health is spreading in the natural mosquito populations, hampering the long-term success of the current vector control strategies. Thus, to achieve the goal of malaria elimination, it appears necessary to improve vector control approaches through the development of novel environment-friendly tools. Mosquito microbiota has by now given rise to the expansion of innovative control tools, such as the use of endosymbionts to target insect vectors, known as "symbiotic control." In this review, we will present the viral, fungal and bacterial diversity of Anopheles mosquitoes, including the bacteriophages. This review discusses the likely interactions between the vector microbiota and its fitness and resistance to insecticides. [ABSTRACT FROM AUTHOR]

In June 2021, scientists celebrated the numerous achievements of a unique collaboration between researchers from the UK and Africa and the UK's national synchrotron, Diamond Light Source [[1]]. The highlight of the research was done by START PDRA Dr. Andani Mulelu, Angela Kirykowicz, and START Co-I Dr. Jeremy Woodward, who visualized a plant nitrilase and were able to explain and modify the substrate specificity of these enzymes. Creating an Africa Block Allocation Group (BAG) at Diamond with START-trained PDRAs assisting with the handling of samples. Here, START PDRAs Dr. Blake Balcomb and Dr. Anton Hamann design medicines to treat tuberculosis, malaria, and S. aureus infections using fragment-based drug discovery resources on the XChem beamline at Diamond. [Extracted from the article]

The emerging understanding of Plasmodium vivax as an infection seated in extravascular spaces of its human host carries fundamentally important implications for its management as a complex clinical and public health problem. This progress begins to reverse decades of neglected research borne of the false dogma of P. vivax as an intrinsically benign and inconsequential parasite. This Review provides real world context for the on-going laboratory explorations of the molecular and cellular events in the life of this parasite. Chemotherapies against the latent reservoir impose extraordinarily complex and difficult problems of science and medicine, but great strides in studies of the biology of hepatic P. vivax promise solutions. Fundamental assumptions regarding the interpretation of parasitaemia in epidemiology, clinical medicine, and public health are being revisited and reassessed in light of new studies of P. vivax cellular/molecular biology and pathogenesis. By examining these long overlooked complexities of P. vivax malaria, we open multiple new avenues to vaccination, chemoprevention, countermeasures against transmission, epidemiology, diagnosis, chemotherapy, and clinical management. This Review expresses how clarity of vision of biology and pathogenesis may rationally and radically transform the multiple means by which we may combat this insidiously harmful infection. [ABSTRACT FROM AUTHOR]

Recent progress in genomics and molecular genetics has empowered novel approaches to 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. CRISPR/Cas9 and other site-specific gene-editing techniques enable rapid and efficient generation of knockouts, targeted integrants, and allelic replacements of genes associated with malaria pathogenesis and drug resistance. Regulatable genetic systems that quantitatively and temporally modulate expression levels facilitate mechanistic studies, especially those involving essential genes, and help distinguish on-target from off-target effects. New or refined whole-genome-based strategies, such as functional genomic screens and genetic crosses in humanized mice, now accompany traditional techniques, including genome-wide association studies (GWAS) and gene editing to identify and characterize genetic determinants of resistance. [ABSTRACT FROM AUTHOR]

Studying malaria transmission biology using scRNA-sequencing provides information on within-host strain diversity and transcriptional states. Here, we comment on our collaborative efforts at establishing single-cell capacities in sub-Saharan Africa and the challenges encountered in Mali's endemic setting. [ABSTRACT FROM AUTHOR]

Advances in research over the past few decades have greatly improved metabolomics-based approaches in studying parasite biology and disease etiology. This improves the investigation of varied metabolic requirements during life stages or when following transmission to their hosts, and fulfills the demand for improved diagnostics and precise therapeutics. Therefore, this review highlights the progress of metabolomics in malaria research, including metabolic mapping of Plasmodium vertebrate life cycle stages to investigate antimalarials mode of actions and underlying complex host-parasite interactions. Also, we discuss current limitations as well as make several practical suggestions for methodological improvements which could drive metabolomics progress for malaria from a comprehensive perspective. [ABSTRACT FROM AUTHOR]

Malaria is one of the most devastating infectious diseases of humans. It is problematic clinically and economically as it prevails in poorer countries and regions, strongly hindering socioeconomic development. The causative agents of malaria are unicellular protozoan parasites belonging to the genus Plasmodium. These parasites infect not only humans but also other vertebrates, from reptiles and birds to mammals. To date, over 200 species of Plasmodium have been formally described, and each species infects a certain range of hosts. Plasmodium species that naturally infect humans and cause malaria in large areas of the world are limited to five—P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The first four are specific for humans, while P. knowlesi is naturally maintained in macaque monkeys and causes zoonotic malaria widely in South East Asia. Transmission of Plasmodium species between vertebrate hosts depends on an insect vector, which is usually the mosquito. The vector is not just a carrier but the definitive host, where sexual reproduction of Plasmodium species occurs, and the parasite's development in the insect is essential for transmission to the next vertebrate host. The range of insect species that can support the critical development of Plasmodium depends on the individual parasite species, but all five Plasmodium species causing malaria in humans are transmitted exclusively by anopheline mosquitoes. Plasmodium species have remarkable genetic flexibility which lets them adapt to alterations in the environment, giving them the potential to quickly develop resistance to therapeutics such as antimalarials and to change host specificity. In this article, selected topics involving the Plasmodium species that cause malaria in humans are reviewed. [ABSTRACT FROM AUTHOR]

Research on Plasmodium parasites has driven breakthroughs in reducing malaria morbidity and mortality. Experimental analysis of in vivo / ex vivo versus in vitro samples serve unique roles in Plasmodium research. However, these distinctly different environments lead to discordant biology between parasites in host circulation and those under laboratory cultivation. Here, we review how in vitro factors, such as nutrient levels and physical forces, differ from those in the human host and the resulting implications for parasite growth, survival, and virulence. Additionally, we discuss the current utility of direct-from-host methodologies, which avoid the potentially confounding effects of in vitro cultivation. Finally, we make the case for methodological improvements that will drive research progress of physiologically relevant phenotypes. Standard in vitro culture environments differ dramatically from in vivo conditions in nutrient levels, hematocrit, and rheology and have lower variability in gas levels and temperature. Nutritional and physical differences lead to pronounced, and often rapid, changes in phenomenon, important for understanding virulence in Plasmodium. Parasite drug sensitivity may be altered due to culture adaptation selection, supraphysiological metabolite concentrations, and in vitro media formulations. Parasites propagated in vitro , versus in vivo , show altered transcriptomic and genomic patterns related to virulence factors, metabolism, gametocytogenesis, and more. Direct-from-host methodologies avoid the impacts of in vitro culture adaptation but limit the types of assessments that can be performed as many experiments either require equipment not readily available in endemic settings or necessitate long-term manipulation. [ABSTRACT FROM AUTHOR]

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. Plasmodium vivax infection is present across most of the malaria-endemic world. P. vivax relapses, arising from dormant liver stages, cause recurrent episodes of malaria that are the main determinant of significant morbidity, mortality, and ongoing transmission. In coendemic areas, where intense malaria-control activities have reduced the burden of P. falciparum , there has been a rise in the proportion of malaria attributable to P. vivax. There is an increased risk of P. vivax after the treatment of P. falciparum in coendemic regions, suggesting potential benefit of universal radical cure for both parasites in some areas. Novel host and parasite diagnostics, single-dose tafenoquine, and short-course primaquine regimens offer hope for safer and more effective radical cure to eliminate the parasite. [ABSTRACT FROM AUTHOR]

The larval environment of holometabolous insects determines many adult life history traits including, but not limited to, rate and success of development and adult lifespan and fecundity. The ancient stress signaling hormone abscisic acid (ABA), released by plants inundated with water and by leaf and root fragments in water, is likely ubiquitous in the mosquito larval environment and is well known for its wide ranging effects on invertebrate biology. Accordingly, ABA is a relevant stimulus and signal for mosquito development. In our studies, the addition of ABA at biologically relevant levels to larval rearing containers accelerated the time to pupation and increased death of A. stephensi pupae. We could not attribute these effects, however, to ABA-dependent changes in JH biosynthesis-associated gene expression, 20E titers or transcript patterns of insulin-like peptide genes. Adult females derived from ABA-treated larvae had reduced total protein content and significantly reduced post blood meal transcript expression of vitellogenin , effects that were consistent with variably reduced egg clutch sizes and oviposition success from the first through the third gonotrophic cycles. Adult female A. stephensi derived from ABA-treated larvae also exhibited reduced lifespans relative to controls. Collectively, these effects of ABA on A. stephensi life history traits are robust, durable and predictive of multiple impacts of an important malaria vector spreading to new malaria endemic regions. [ABSTRACT FROM AUTHOR]

Mosquito‐borne diseases cause a major burden of disease worldwide. The vital rates of these ectothermic vectors and parasites respond strongly and nonlinearly to temperature and therefore to climate change. Here, we review how trait‐based approaches can synthesise and mechanistically predict the temperature dependence of transmission across vectors, pathogens, and environments. We present 11 pathogens transmitted by 15 different mosquito species – including globally important diseases like malaria, dengue, and Zika – synthesised from previously published studies. Transmission varied strongly and unimodally with temperature, peaking at 23–29ºC and declining to zero below 9–23ºC and above 32–38ºC. Different traits restricted transmission at low versus high temperatures, and temperature effects on transmission varied by both mosquito and parasite species. Temperate pathogens exhibit broader thermal ranges and cooler thermal minima and optima than tropical pathogens. Among tropical pathogens, malaria and Ross River virus had lower thermal optima (25–26ºC) while dengue and Zika viruses had the highest (29ºC) thermal optima. We expect warming to increase transmission below thermal optima but decrease transmission above optima. Key directions for future work include linking mechanistic models to field transmission, combining temperature effects with control measures, incorporating trait variation and temperature variation, and investigating climate adaptation and migration. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum (Pf) refurbishes the infected erythrocytes by exporting a myriad of parasite proteins to the host cell. A novel exported protein family 'Plasmodium Helical Interspersed Subtelomeric' (PHIST) has gained attention for its significant roles in parasite biology. Here, we have collected and analysed available information on PHIST members to enhance understanding of their functions, varied localization and structure-function correlation. Functional diversity of PHIST proteins is highlighted by their involvement in PfEMP1 (Pf erythrocyte membrane protein 1) expression, trafficking and switching. This family also contributes to cytoadherence, gametocytogenesis, host cell modification and generation of extracellular vesicles. While the PHIST domain forms the hallmark of this family, existence and functions of additional domains (LyMP, TIGR01639) and the MEC motif underscores its diversity further. Since specific PHIST proteins seem to form pairs with PfEMP1 members, we have used in silico tools to predict such potential partners in Pf. This information and our analysis of structural data on a PHIST member provide important insights into their functioning. This review overall enables readers to view the PHIST family comprehensively, while highlighting key knowledge gaps in the field. [ABSTRACT FROM AUTHOR]

Host cell traversal protects the vulnerable sporozoite from phagocytosis, primes the sporozoite through the activation of apical exocytosis, and prepares the motile sporozoite for invasion [[1]]. Cell traversal protein for ookinetes and sporozoites (CelTOS) is a unique I Plasmodium i pore-forming protein that is required for cell traversal in both the mammalian host and the mosquito vector. CeITOS, cell traversal protein for ookinetes and sporozoites; CSP, circumsporozoite protein; PfEBA, Plasmodium falciparum erythrocyte binding antigen; PfRH, Plasmodium falciparum reticulocyte-binding homologue; PLP, perforin-like protein; PSPECT1, sporozoite protein essential for cell traversal 1; PvRBP, Plasmodium vivax reticulocyte-binding proteins; TRAP, thrombospondin-related adhesive protein. Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites. [Extracted from the article]

CRISPR/Cas9 approaches are revolutionizing our ability to perform functional genomics across a wide range of organisms, including the Plasmodium parasites that cause malaria. The ability to deliver single point mutations, epitope tags and gene deletions at increased speed and scale is enabling our understanding of the biology of these complex parasites, and pointing to potential new therapeutic targets. In this review, we describe some of the biological and technical considerations for designing CRISPR-based experiments, and discuss potential future developments that broaden the applications for CRISPR/Cas9 interrogation of the malaria parasite genome. [ABSTRACT FROM AUTHOR]

Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused by the apicomplexan parasite Plasmodium falciparum. Apicomplexan parasites, including the Plasmodium spp., are descendants of photosynthetic algae, and therefore they possess an essential plastid organelle, named the apicoplast. Since humans and animals have no plastids, the apicoplast is an attractive target for drug development. Indeed, after its discovery, the apicoplast was found to host the target pathways of some known antimalarial drugs, which motivated efforts for further research into its biological functions and biogenesis. Initially, many apicoplast inhibitions were found to result in ‘delayed death’, whereby parasite killing is seen only at the end of one invasion-egress cycle. This slow action is not in line with the current standard for antimalarials, which seeded scepticism about the potential of compounds targeting apicoplast functions as good candidates for drug development. Intriguingly, recent evidence of apicoplast inhibitors causing rapid killing could put this organelle back in the spotlight. We provide an overview of drugs known to inhibit apicoplast pathways, alongside recent findings in apicoplast biology that may provide new avenues for drug development. [ABSTRACT FROM AUTHOR]

Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions. This review discusses recent insights into gametocyte biology in the major human malaria parasite, Plasmodium falciparum and related species. [ABSTRACT FROM AUTHOR]