Gotowa bibliografia na temat „Plasmodium falciparum – Dormance”

BACKGROUND The presence of Plasmodium falciparum resistance and decreased efficacy of artemisinin and its derivatives has resulted in the issue of malaria becoming increasingly complex, because there have been no new drugs as artemisinin replacements. The aims of this research were to evaluate in vitro changes in ultrastructural morphology of P. falciparum 2300 strain after exposure to artemisinin. METHODS The research used an experimental design with post test only control group. Cultures of P. falciparum 2300 strain in one control and one mutant group were treated by exposure to artemisinin at IC50 10-7 M for 48 hours. Ultrastructural phenotypic examination of ring, trophozoite and schizont morphology and developmental stage in the control and mutant group were done at 0, 12, 24, 36, 48 hours by making thin blood smears stained with 20% Giemsa for 20 minutes and examined using a microscope light at 1000x magnification. RESULTS Dormant forms occurred after 48 hours of incubation with IC50 10-7 M artemisinin in the control group. In the mutant group, dormant forms, trophozoites with blue cytoplasm and normal schizont developmental stages were seen. Ultrastructural phenotypic morphology at 0, 12, 24, 36, 48 hours showed that in the control group dormant formation already occurred with exposure to IC50 10-7 M, while in the mutant group dormant formation occurred only with exposure to IC50 2.5x10-5 M. CONCLUSION Exposure to artemisinin antimalarials in vitro can cause phenotypic morphological changes of dormancy in P. falciparum Papua 2300 strain.

ABSTRACTThein vitroantimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy inPlasmodium falciparum. There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistantP. falciparumlines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings.

ABSTRACTFor a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems—primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC50) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells and, likewise, had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.

ABSTRACTArtemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways inP. falciparumduring dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.

ABSTRACTIn vitrodrug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage inPlasmodium falciparum. This response has been proposed to play a role in the recrudescence ofP. falciparuminfections following monotherapy with artesunate and may contribute to the development of artemisinin resistance inP. falciparummalaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest ofP. falciparumparasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage ofP. falciparumand prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistantP. falciparummalaria.

ABSTRACTThe appearance ofPlasmodium falciparumparasites with decreasedin vivosensitivity but no measurablein vitroresistance to artemisinin has raised the urgent need to characterize the artemisinin resistance phenotype. Changes in the temporary growth arrest (dormancy) profile of parasites may be one aspect of this phenotype. In this study, we investigated the link between dormancy and resistance, using artelinic acid (AL)-resistant parasites. Our results demonstrate that the AL resistance phenotype has (i) decreased sensitivity of mature-stage parasites, (ii) decreased sensitivity of the ring stage to the induction of dormancy, and (iii) a faster recovery from dormancy.

Abstract Plasmodium falciparum relies on anion channels activated in the erythrocyte membrane to ensure the transport of nutrients and waste products necessary for its replication and survival after invasion. The molecular identity of these anion channels, termed “new permeability pathways” is unknown, but their currents correspond to up-regulation of endogenous channels displaying complex gating and kinetics similar to those of ligand-gated channels. This report demonstrates that a peripheral-type benzodiazepine receptor, including the voltage dependent anion channel, is present in the human erythrocyte membrane. This receptor mediates the maxi-anion currents previously described in the erythrocyte membrane. Ligands that block this peripheral-type benzodiazepine receptor reduce membrane transport and conductance in P falciparum-infected erythrocytes. These ligands also inhibit in vitro intraerythrocytic growth of P falciparum. These data support the hypothesis that dormant peripheral-type benzodiazepine receptors become the “new permeability pathways” in infected erythrocytes after up-regulation by P falciparum. These channels are obvious targets for selective inhibition in anti-malarial therapies, as well as potential routes for drug delivery in pharmacologic applications.

Plasmodium ovale is a cause of non-falciparum malaria infection that is endemic in tropical Western Africa. The life cycle of Plasmodium ovale includes hypnozoites, which are dormant stages in the liver. These stages can be reactivated after weeks, months, or years from the initial infection, causing disease relapse. This paper reports the case of a female adolescent who presented with high fever and abdominal pain. The girl was referring to a single travel to Nigeria 4 years ago. On that occasion she showed short-term gastrointestinal symptoms, without fever. The blood test revealed thrombocytopenia (76,000/µl) and she was unexpectedly diagnosed with ma-laria through blood smear. Considering the geographical area of her previous travel, a parasitemia by Plasmodium ovale was suspected. The diagnosis was soon confirmed by the positivity of the PCR. The literature describes some cases of recrudescence of the infection from the first episode. The diagnosis of Plasmodium ovale malaria can be challenging because of its possible delayed presentation.

ABSTRACT The occurrence of Plasmodium vivax resistance to chloroquine has been reported in several countries of Asia and South America. However, the resistance of P. vivax is insufficiently documented for three reasons: it has received far less attention than P. falciparum; in vivo investigations are handicapped by the existence of hypnozoites, which make it difficult to distinguish between recrudescences due to drug failure and relapses due to dormant forms in the liver; and in vitro studies are greatly limited by the poor growth of P. vivax. We report on the adaptation to P. vivax of a colorimetric double-site Plasmodium lactate dehydrogenase antigen capture enzyme-linked immunosorbent assay previously developed for P. falciparum. The assay proved remarkably sensitive, as under optimal conditions it could detect P. vivax parasitemia levels as low as 10−8. The technique, which relies on the detection of protein synthesis by the parasite, yielded steep drug-response curves, leading to the precise determination of the 50% inhibitory concentrations for a high proportion of isolates. Chloroquine-resistant parasites were identified in an area where this phenomenon had been documented by in vivo methods. Thus, the results indicate that the in vitro susceptibility of P. vivax can now be monitored easily and efficiently. The data suggest that the threshold of resistance is similar to that of P. falciparum, i.e., in the range of 100 nM for chloroquine and 15 nM for pyronaridine. However, further studies are required to precisely define the cutoff for resistance and the sensitivity to each drug.

Plasmodium falciparum est l'agent pathogène responsable des formes les plus graves de paludisme. P. falciparum a été responsable de 619 0000 décès et 247 millions de cas de paludisme dans le monde en 2022. Le parasite possède un cycle de vie complexe qui se déroule chez les moustiques du genre Anophèles et les hôtes humains. L'artémisinine et ses dérivés, associés à des médicaments partenaires, constituent les thérapies combinées à base d'artémisinine (TCA) et sont les traitements les plus efficaces actuellement disponibles. Malheureusement, depuis plus de 15 ans, des souches de P. falciparum originaire d’Asie du Sud-est présentent une résistance partielle à l'artémisinine et menacent les efforts de lutte contre le paludisme. Cette résistance partielle a pu être associée à la présence de mutations au sein du gène Pfkelch13 mais également à un retard de croissance (dormance) induit par l’artémisinine, permettant à une partie des parasites de survivre à la drogue. Cette thèse a pour objectif de mieux comprendre les mécanismes sous-jacents à la résistance à l'artémisinine. Elle s'articule autour de 3 axes incluant la compréhension de l’épidémiologie de la résistance en Afrique, l’amélioration des outils permettant de détecter la résistance et l’étude des mécanismes moléculaires et cellulaires. La première partie décrit l'émergence en Érythrée d'un double mutant Pfkelch13 résistant à l'artémisinine grâce à la mutation R622I mais indétectable par les tests de diagnostic rapide car dépourvu des gènes Pfhrp2 et Pfhrp3. Ces données s'inscrivent dans un récent contexte d'émergence de la résistance de P. falciparum à l'artémisinine à travers le continent africain et soulignent l'urgence de mettre en place de nouvelles stratégies de contrôle. Dans la seconde partie de ce travail, une version optimisée du Ring-Stage Survival Assay, un outil de diagnostic clé pour détecter les souches de P. falciparum résistantes à l'artémisinine, a été développée. Cette optimisation du test permet la synchronisation simultanée de plusieurs souches de P. falciparum avec des profils de croissance in vitro différents, permettant de réaliser en parallèle de manière fiable et reproductible, des tests RSA sur plusieurs souches. La troisième partie s'est concentrée sur l'étude de la dormance induite par l'artémisinine en tant que mécanisme de résistance. Nous avons pu mettre en évidence des changements importants dans le métabolisme des stades rings dormants, basés sur le catabolisme des acides aminés. De plus, nous avons pu faire la lumière sur l'inductibilité de la dormance, chez les parasites au stade ring, par des signaux de stress extracellulaires libérés lors de la mort de parasites matures. Enfin, des données préliminaires d’analyse transcriptomique à l’échelle de l’individu a révélé l’existence d’une étonnante diversité parmi les stades rings synchrones et issus d'une souche clonale. Finalement, l'ensemble des données présentées ici suggèrent que la dormance est un mécanisme constitutif chez le stade ring de P. falciparum, dépendant de l'exposition à des signaux extracellulaire de nature et concentration inconnue, indépendant du génotype Pfkelch13. Nous sommes convaincus que ces travaux peuvent servir de base au développement de nouvelle stratégie thérapeutique, basée sur la perturbation des communications extracellulaires du parasite, l'inhibition de l'entrée en dormance et le maintien du parasite dans un état de susceptibilité à l'artémisinine
Plasmodium falciparum is the causative agent of the most severe form of malaria. In 2022, the disease was responsible for 619,000 deaths and 247 million cases worldwide. P. falciparum has a complex life cycle in the mosquito vector and in the human host. Artemisinin and its derivatives are used in combination with partner drugs. Artemisinin-based combination therapies (ACT) are currently the most effective treatment available. Unfortunately, malaria control efforts are threatened by mutations in the Pfkelch13 gene of P. falciparum, which confer partial resistance to artemisinin. This resistance to artemisinin is also associated with a drug-induced dormancy phenotype, which allows a proportion of parasites to survive exposure to the drug. This thesis focuses on artemisinin resistance and drug-induced dormancy through a multidisciplinary approach. It combines public health, technical optimisation and basic research. As part of the public health work, we have detected the emergence of a new double mutant Pfkelch13-R622I resistant to artemisinin in patients in Eritrea. This mutant is associated with deletions in the Pfhrp2 and Pfhrp3 genes, reducing the performances of HRP2-based rapid diagnostic tests. These data highlight the urgency of developing new control strategies in the context of the emergence of artemisinin resistance across the African continent. An optimised version of the Ring-Stage Survival Assay, the main diagnostic tool used to detect artemisininresistant P. falciparum parasites, was developed. This optimisation allows for the simultaneous synchronisation of several P. falciparum strains with different genetic backgrounds, thus enabling multiple RSA tests to be performed in parallel in a reliable and reproducible manner. Finally, basic research focused on studying drug-induced dormancy as a mechanism of artemisinin resistance. We were able to demonstrate important changes in the metabolism of dormant ring stage parasites based on amino acid catabolism. We have also shown that dormancy can be induced by extracellular stress signals released by dying mature stage parasites. Finally, our data indicate that the synchronous early ring stage of a clonal parasite population exhibits high transcriptional diversity. All the data presented suggest that dormancy is a constitutive mechanism at P. falciparum ring stage, mediated by extracellular signals of an unknown nature and concentration, independent of Pfkelch13 genotypes. We are convinced this work may provide a basis for developing a new therapeutic strategy based on interfering with the parasite's extracellular communications

The causative agent of malignant tertian malaria, Plasmodium falciparum undergoes an arrested growth phenotype of its erythrocytic stage when under drug-stress. Recent artemisinin treatment failures seem to be indicative of such induction followed by recrudescence rather than actual therapeutic failure. Likewise, P. vivax hypnozoites are the prototypic dormants and the latent infections for which they are responsible prove most difficult to treat. Dihydroartemisinin, an artemisinin-derivative, can be used to exploit this mechanism by inducing a dormant state in ring-stage P. falciparum parasites and in turn, their recovery may be used as a screening period for compounds that inhibit or foster growth. Specifically, parasites stably transfected with luciferase were used to quantitatively observe growth (or lack thereof) response of parasites to the phytohormone gibberellic acid and the herbicide, fluridone. Using their behavior as comparative controls, the Medicines for Malaria Venture (MMV) Malaria Box was screened for similar activity. The most active compound, 1,2,3,4-tetrahydroacridin-9-ol a quinoline-derivate caused cells to wake even earlier than expected. Since quinine and other such drugs have historically been most effective in treating malaria, it seems appropriate that such a finding was made. Following this the MMV Box was screened again against uninduced 3D7 parasites to determine if any were capable of causing a dormant response under the hypothesis that such a reaction is a defensive adaptation of P. falciparum. Four compounds were found to be active of which two appear to be inducing dormancy in the second cycle rather than the first akin to DHA. These quiescent periods also appear to be shorter indicating that the latter is more efficient. It is possible that given the length of interaction with artemisinin, P. falciparum is more adept to respond to its derivatives likewise the mechanism of action may be different enough to change the nature of the response.

Combating drug resistant malaria has been historically challenging, and remains so today. Recent reports from Southeast Asia show that Plasmodium falciparum is developing resistance to even our best defenses; artemisinin-based therapies. This development threatens to become a significant challenge in controlling malaria infections worldwide, making research into developing and characterizing new antimalarial drugs increasingly important. The purpose of this study was to characterize the resistance potential of novel antimalarial compound JPC-3210 in vitro using P. falciparum clones. JPC-3210 is a new long acting drug with potential to be used in combination with fast-acting drugs like artemisinins to cure drug resistant malaria. In this study several methods were used to characterize the efficacy and resistance potential of JPC-3210. To determine the frequency of resistance generation in P. falciparum clones, parasites were kept under continuous drug pressure for thirty days, at which point drug pressure was removed and cultures were observed for signs of recrudescence. P. falciparum clones also were exposed to increasing levels of intermittent drug pressure that involved 3-4 days of drug exposure followed by a recovery period. The step-wise experiment was conducted over three months with drug pressure being increased step-wise until a maximal concentration of 700 ng/ml of JPC-3210; resistance was measured phenotypically in drug susceptibility assays at multiple time points. Additionally, the ability of JPC-3210 to induce dormant stage parasites, and its effect on dihydroartemisinin (DHA)-induced dormant stages was assessed in both a chloroquine resistant parasite (W2) and in an artemisinin resistant clone (4G). Results showed that the frequency of resistance against JPC-3210 in W2 clones was less when compared to that of atovaquone. The step-wise pulse exposure of JPC-3210 induced resistance in W2 clones, however, resistance proved unstable. Dormant stage parasites were not induced by JPC-3210, even at high concentrations in W2 or 4G clones, furthermore, the effect of JPC-3210 on dormant-induced parasites was found to be dose dependent, yet the drug did not kill DHA-induced dormant rings. JPC-3210 appears to be a good drug to use in combination with other antimalarial compounds for treatment of P. falciparum, but further research is needed. Future studies to assess the field performance of new antimalarial compounds by investigating resistance and dormancy profiles in vitro, and thereby maximizing out understanding of such drugs and their optimal implementation, are of the utmost importance.

Our ability to control malaria has been challenged by increasing antimalarial resistance. Plasmodium falciparum undergoes dormancy in the blood stages which is hypothesized to be a means by which they are able to survive under drug pressure. This helps select for resistant parasites which grow following removal of drug. The mechanisms behind dormancy and the subsequent recrudescence are not fully understood but translating knowledge from related organisms which undergo a similar phenomenon might shed some light. Higher plants utilize dormancy during the early development stages to survive under unfavorable conditions, increasing fitness of the seedling and ensuring viability when this is released and it develops into a mature plant. Abscisic acid (ABA) and gibberellic acid (GA) antagonistically regulate this in response to environmental cues. We have found that both can be supplemented to dihydroartemesinin-induced dormant parasites to stimulate early recovery. Fluridone, an ABA inhibitor that releases dormancy in plants, was found to prolong it and cause a delay in recrudescence. These effects were observed in artemisinin sensitive and resistant strains. The apicoplast is required for recovery and supplementation of essential isoprenoid, isopentyl pyrophosphate (IPP), in apicoplast deficient parasites is sufficient enough to compensate for the lack of the organelle in antibiotic treated parasites. IPP plays an important role in development and metabolism of blood stage parasites as a key component of numerous secondary metabolites and protein activity by prenylation of isoprenoids. Its role in dormancy has not been explored prior to this study. Carotenoids are long-chained ABA precursors consisting of two molecules of geranylgeranyl pyrophosphate (GGPP). Several carotenoids as well as enzymes in that pathway have been identified in the blood stages of P. falciparum. The Apicomplexan parasite, Toxoplasma gondii synthesizes ABA, where it plays a role in signaling and development. To date ABA has not been detected in P. falciparum due to limitations in methods previously utilized. We have found that parasites with fosmidomycin inhibition of isoprenoids can be rescued with GGPP supplementation which we planned to use to further elucidate the carotenoid biosynthetic pathway. We hypothesized that Plasmodium has retained the ability to biosynthesize ABA and aimed to confirm this. We developed a novel method to label GGPP with 13C on three of its isoprene units. This would be used to metabolically label isoprenoid inhibited P. falciparum for incorporation through the carotenoid pathway for detection of 13C-ABA.

Plasmodium vivax being the most geographically spread Plasmodium species is considered sparsely distributed in sub-Saharan Africa (sSA) while P. falciparum is the most prevalent species in this region. Thus, control strategies in sSA have been disproportionately targeted towards falciparum malaria. Nevertheless, with the use of more sensitive malaria diagnostic platforms, there are more reports of P. vivax and other non-falciparum malaria in sSA. In addition, P. vivax is presumed benign, however there are new findings of severe cases recorded from P. vivax single or mixed infection with other Plasmodium species. Besides, the extended dormant period (lasting for weeks or months) is a challenge for achieving effective cure for vivax infections. Although, chloroquine has been proscribed for treatment P. falciparum, it still remains the drug of choice for P. vivax in most Asian countries where it is predominant. In sSA, artemisinin combination-based therapies (ACTs) are used for treatment of falciparum malaria and, it is probable that the use of ACT could be enhancing adaptive selection for P. vivax in the face of its increasing prevalence in the population. Hence, understanding epidemiological and biological factors, and data that could be contributing to the observed steady increase in P. vivax prevalence in sSA is important. In this chapter, we discuss the mechanisms for invasion of red blood cells, trends in increasing prevalence of vivax malaria, diagnostic tools, and the public health implications of P. vivax and P. falciparum co-endemicity in Africa.

Malaria is a global public health issue. Despite the efforts in malaria prevention, nearly half the world’s population is at risk of infection. Until present-day, researchers are struggling to design and discover an efficacious antimalarial. In comparison to most common antimalarial chemotypes that eliminate erythrocytic stages of P. falciparum, 4(1H)-quinolones and 4(1H)-pyridones exhibit antimalarial activity against multiple stages of the parasite. They have potential to treat blood stages of multidrug resistant P. falciparum malaria, eradicate dormant exoerythro stages of relapsing malaria species (P. vivax), and prevent transmission of infectious gametocytes to mosquitoes. However, thus far, the advancement of these chemotypes towards pre-clinical and clinical development has been impeded due to poor physicochemical properties, poor oral bioavailability, and poor dose-proportionality limiting preclinical safety and toxicity studies. Despite all these challenges, 4(1H)-quinolones and 4(1H)-pyridones continue to be at the forefront for the development of the next-generation antimalarials as they would have tremendous global public health impact and could significantly enhance current malaria elimination efforts.

Malaria is caused by multiple parasitic species of the genus Plasmodium. Although P. falciparum accounts for the highest mortality, P. vivax is the most geographically dispersed and the most common species outside of Africa. Several unique biological features make P. vivax less responsive to conventional control measures and allow it to persist even after elimination of P. falciparum. The ability of P. vivax to develop in diverse vectors at lower ambient temperatures bestows it a greater distribution range and resilience to ecological changes. Its tropism for reticulocytes often causes low-density infections below the levels detectable by routine diagnostic tests, demanding the development of more sensitive diagnostics. P. vivax produces gametocytes early enabling transmission before the manifestation of clinical symptoms, thus emphasizing the need for an integrated vector control strategy. More importantly, its dormant liver stage which engenders relapse is difficult to diagnose and treat. The deployment of available treatments for the liver hypnozoites, including primaquine and the recent U.S. Food and Drug Administration-approved tafenoquine, requires point-of-care diagnostics to detect glucose-6-phosphate dehydrogenase deficiency among endemic human populations. Here we review the continued challenges to effectively control P. vivax and explore integrated technologies and targeted strategies for the elimination of vivax malaria.

Malaria is a tropical parasitic infection of the red blood cells caused by the protozoal species Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. It is transmitted through the bite of the female Anopheles mosquito. The average incubation period is twelve to fourteen days. Congenital and blood-borne transmissions can also occur. P. falciparum and P. vivax account for most human infections but almost all deaths are caused by P. falciparum, with children under five years of age bearing the brunt of morbidity and mortality in endemic countries. P. falciparum is dominant in sub-Saharan Africa whereas P. vivax predominates in Southeast Asia and the Western Pacific. P. ovalae and P. malaria are less common and are mainly found in sub-Saharan Africa. P. knowlesi primarily causes malaria in macaques and is geographically restricted to southeast Asia. While taking a blood meal, the female anopheline mosquito injects motile sporozoites into the bloodstream. Within half an hour, the sporozoites invade the hepatocytes and start dividing to form tissue schizonts. In P. vivax and P. ovale, some of the sporozoites that reach the liver develop into hypnozoites and stay dormant within the hepatocytes for months to years after the original infection. The schizonts eventually rupture releasing daughter merozoites into the bloodstream. The merozoites develop within the red blood cells into ring forms, trophozoites, and eventually mature schizont. This part of the life cycle takes twenty-four hours for P. knowlesi; forty-eight hours for P. falciparum, P. vivax, P. ovale; and seventy-two hours for P. malariae. In P. vivax and P. ovale, some of the sporozoites that reach the liver develop into hypnozoites and stay dormant within the hepatocytes for months to years after the original infection. The hallmark of malaria pathogenesis is parasite sequestration in major organs leading to cytoadherence, endothelial injury, coagulopathy, vascular leakage, pro-inflammatory cytokine production, and tissue inflammation. Malaria is the most frequently imported tropical disease in the UK with an annual case load of around 2000. P. falciparum is the predominant imported species, and failure to take chemoprophylaxis is the commonest risk factor.

Each year, approximately 230 million malaria cases and 400,00 malaria deaths are reported worldwide. Malaria is a life-threatening disease caused by Plasmodium parasites that are transmitted from one individual to another through the bites of infected female Anopheles mosquitoes. Malaria parasites replicate asexually in the human host, and, in each replication cycle, a portion of the asexual stages develops into sexual gametocytes that permit transmission. The proportion of infections that carries gametocytes and the infectivity of gametocytes are indicators of human-to-mosquito transmission potential. In P. falciparum, gametocytes appear 10–14 days after infection, whereas in P. vivax gametocytes appear simultaneously with asexual schizonts. Such difference in development not only increases the length of time that an individual is infectious, but also increases the likelihood of transmission before treatment. The conversion from asexual parasites to gametocytes is also highly variable between infections. Differences in age, host immune response, parasite genetic composition, density of red blood cells, presence of co-infecting parasite strains, and antimalarial drug use could affect gametocytes production. In P. vivax, the unique ability to produce hypnozoites, a dormant liver stage of the parasite, may allow gametocytes to be produced periodically from relapse and contribute to transmission. In this chapter, we will provide an overview of the biology of Plasmodium gametocytes, existing tools for gametocyte detection, and features of gametocyte genes. The biological insights and genetic findings are essential to developing better detection biomarkers and effective strategies to reduce transmission in malaria-endemic countries.