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Plasmodium actin was highly purified by gel filtration of crude G-actin on Sephadex G-100 followed by ultracentrifugation after polymerization in the presence of 1 M urea and 1 mM ATP. Purified actin showed a single band in the sodium dodecyl sulfate gel electrophoretic pattern. Antibody against this purified actin was induced in rabbits. The antibody obtained was immunologically monospecific for plasmodium actin, judging from the following results. (1) The addition of the antibody to a plasmodium F-action solution increased the turbidity of the mixed solution, showing the formation of the antibody-action complex. (2) In immunodiffusion and immunoelectrophoresis, the antibody formed single preciptin lines with the purified actin preparation and with the crude actin extract from the acetone-dried powder of plasmodium. (3) The antibody inhibited polymerization of plasmodium G-actin. (4) Plasmodium F-actin filaments were decorated with antibody in electron micrographs. The antibody reacted not only with plasmodium F- and G-actin, but also reacted with sea urchin egg actin, but it did not react with actin from rabbit striated muscle.
Groups of mice were inoculated with either low or high intraperitoneal doses of Plasmodium berghei infected erythrocytes (PIE). The course of infection was observed daily by counting new PIE which appeared in the red blood cells (RBC) of infected mice. At the same time, circulating interferon (IF) was tested. When low doses of infecting PIE were used (400 per mouse), circulating IF was first detected on the 5th day after inoculation. It increased to a maximal rate, when 5% of RBC were affected. It disappeared on the 8th day despite of a continuous rise of PIE. With high doses of PIE (60,000 per mouse), IF was detected on the 3rd day, when only 0.5% of RBC were parasitized. The maximal rate was observed on the 5th day when 20% of the RBC were affected. It disappeared on the 7th day, though the PIE rate would continue to rise. Treatment of mice by chloroquine (0.01 per g), at the time of first PIE appearance after Plasmodium infection, rapidly reduced the amount of PIE. In this case, no IF production was observed. Splenectomy resulted in an increased resistance of mice to the lethal effect of Plasmodium infection. IF production in such splenectomized mice was less important than in control. It was concluded that P. berghei was a good inducer of circulating IF at the beginning of the active disease, soon after infection. The fact was proven by the striking lowering effect of chloroquine and splenectomy that both reduced Plasmodium development and IF production.
Invasion of immature and mature erythrocytes by merozoites of Plasmodium berghei seems to obey the following rules: Merozoites prefer unparasitized immature erythrocytes. Multiple infections of immature erythrocytes occur in conditions of high merozoite production and low concentration of unparasitized immature erythrocytes, when frequently repeated contacts between merozoites and unparasitized or freshly parasitized immature erythrocytes become increasingly probable. Mature erythrocytes are invaded when the relative density of unparasitized immature erythrocytes drops below 0.2--0.5%, in other words, when merozoites do not meet unparasitized immature erythrocytes in 200--500 erythrocytes. Failure to invade mature erythrocytes is obviously not due to inability of the merozoites to penetrate the erythrocyte membranes.--Merozoites of Plasmodium vinckei, on the other hand, show random invasion of parasitized and unparasitized mature erythrocytes, leading to frequencies of unparasitized and singly or multiply parasitized erythrocytes approaching a Poisson distribution.--The Plasmodium berghei infection regularly leads to a lowered density of polychromatophilic erythrocytes in the peripheral blood. This depression of polychromatophilic erythrocytes uses to be of very different duration, form and intensity. The relative density of immature erythrocytes may show pronounced fluctuations in this phase. As has been seen in one animal, even monocytes and polymorphonuclear leucocytes may, alongside with the immature erythrocytes, for some time totally disappear from the peripheral blood. The depression of polychromatophilic erythrocytes evidently goes along with pronounced alterations of the erythropoesis in spleen and bone marrow. Leucocytes in the peripheral blood generally show rather uncharacteristic alterations of their concentration, they may form very high concentration peaks.
Plasmodium ovale as the causative parasite in attacks of malaria is rare. Nevertheless, the number of cases seen in France would seem to be on the increase. In 137 attacks of malaria collected between 1967 and 1978, Plasmodium ovale was found on 13 occasions. The main characteristics of this form of malaria are, apart from its benign nature, the usual absence of any recurrence and a very variable incubation period, ranging from fifteen days to several months or even a year (with an average of 3.2 months). It is thus important to bear this diagnosis in mind, even if a long period elapsed since return from an endemic area, and it will be realised that adequate chemoprophylaxis using a schizonticide does not offer protection from forms with a long incubation period. Genetic control of the duration of the period of maturation of exo-erythrocytic forms, i.e. the incubation period, is suggested, identical to that recently advanced in the case of Plasmodium vivax. This would account for the variability and possible long duration of incubation periods. A usual monoclonal character of these infections could explain the virtual absence of recurrences.
This paper describes the fine structure of the sporogonic development of Plasmodium falciparum in its natural vector Anopheles gambiae (Species A) as seen by scanning and transmission electron microscopy. The parasite was derived from naturally infected volunteers and the vector maintained under natural conditions at the MRC Laboratories, Fajara, The Gambia. Sporogonic development of P. falciparum is similar to that described for other Plasmodium spp. There are however greater similarities between P. falciparum and the avian malaria parasites, than those mammalian (primarily rodent) species described to date--particularly with respect to mitochondrial development, crystalloid morphology and nucleolar organization. Nuclear development is similar to that of the murine malaria parasites, but reconstruction of complete mitotic spindles from serial sections suggest the haploid genome of P. falciparum contains 14 chromosomes compared to eight to ten in the murine plasmodia. Sporoblast formation involves a unique process of cleft formation based on the expansion of the cisternal space of the endoplasmic reticulum. Sporozoite budding is almost exclusively confined to these inner membrane surfaces and results in a characteristic sporozoite distribution in the oocyst. High resolution scanning electron microscopy of free sporozoites provides the first surface view of the micropore of Plasmodium.
The creation of transgenic Plasmodium falciparum lines with robust fluorescence across the entire life cycle is essential for advancing our understanding of parasite biology, which in turn informs the development of new drugs and vaccines. In this study, we utilized Plasmodium-optimized genome editing to integrate an mCherry expression cassette into a selected intergenic locus without gene disruption. The resulting marker-free line, NF54-mCh, exhibited intense fluorescence throughout all developmental stages, including asexual and sexual blood stages, as well as mosquito (ookinete, oocyst, and sporozoite) and liver stages. NF54-mCh showed normal proliferation, gametocytogenesis, and efficient transmission to mosquitoes. The ultra-high brightness in salivary gland sporozoites allowed for the non-invasive identification of infected mosquitoes. Sporozoites remained highly infectious to humanized mouse livers, thus enabling the completion of the full life cycle. NF54-mCh serves as a parental line for performing additional genetic modifications, because the CRISPR/Cas9-based genome editing method is free of introduced drug resistance markers. The broader applicability of this strategy was validated by generating similar reporter lines in Plasmodium species utilized in rodent malaria models. In summary, NF54-mCh represents a unique, versatile platform that will accelerate fundamental research and support the future development of malaria control strategies, including new vaccines and drugs.
The human malaria parasite Plasmodium falciparum evolved from a parasite that infects gorillas, termed Plasmodium praefalciparum. The sialic acids on glycans on the surface of erythrocytes differ between humans and other apes. It has recently been shown that the P. falciparum cysteine-rich protective antigen (PfCyRPA) binds human sialoglycans as an essential step in the erythrocyte invasion pathway, while that of the chimpanzee parasite, Plasmodium reichenowi has affinities matching ape glycans. Two amino acid changes, at sites 154 and 209, were shown to be sufficient to switch glycan binding preferences and inferred to reflect adaptation of P. falciparum to humans. However, we show that sites 154 and 209 are identical in P. falciparum and P. praefalciparum, with no other differences located in or near the CyRPA glycan binding sites. Thus, the gorilla precursor appears to have already been preadapted to bind human sialoglycans.
Plasmodium (Giovannolaia) durae Herman was originally described from Kenya, the type host being the common turkey, Meleagris gallopavo Linnaeus. There are no field records of this association outside of Africa, where the parasite, herein reported from another introduced and domesticated bird (the common peafowl, Pavo cristatus Linnaeus), was recently listed from 2 native Phasianidae of the genus Francolinus. The justification for the present identification is submitted against background data concerning malaria parasites from turkeys and other Galliformes in Africa and elsewhere, and restraint is urged in describing yet more "new species" of avian Plasmodium belonging to morphologically close taxa within Novyella and Giovannolaia. A near relative of P. durae, Plasmodium dissanaikei de Jong, is transferred from the former subgenus to the latter one.
World literature on Plasmodium of squamate reptiles (1909-1975) includes 156 published accounts on 54 valid species and subspecies. AFRICA: 30 reports on 9 species; AUSTRALIA, ASIA & OCEANIA: 12 reports on 6 species and 2 subspecies; AMERICAS: 116 reports on 37 species. More than half of these reports and new species descriptions appeared during the last 10 years. Most concern plasmodia in lizards of the Neotropics, Georgia (Plasmodium floridense, a Neotropical-Caribbean parasite) and California (Plasmodium mexicanum). African host species are all lizards: 4 agamids, 3 skinks, 2 chamaeleonids, one chordyline, and one gerrhosaurine. Australasian host species are also all lizards: 6 agamids, 9 skinks, 2 lacertids, one (or two?) gekkonids, and one varanid. Known American host species include 12 snakes and 87 lizards: 34 anoline species, 12 sceloporines (plus 11 others experimentally infected), 4 basiliscines, 5 tropidurines, 2 iguanines, 2 skinks (one questionable), 2 anguids (a total of 4 animals), 4 sphaerodactylines, 2 gekkonines and 11 teiid species.
The kinetics of sickling of malaria-infected red cells from humans with sickle cell trait were studied in vitro in an attempt to obtain direct experimental evidence for a selective advantage of the hemoglobin S heterozygote in a malarious region. The sickling rates of cells infected with Plasmodium falciparum and of non-infected cells were studied both in the total absence of oxygen (by dithionite addition) and at several different concentrations of oxyhemoglobin which might obtain in vivo. In all cases, red cells containing small plasmodium parasite forms (ring forms) sickled approximately eight times as readily as uninfected cells. Cells containing large parasitic forms (trophozoites and schizonts) appeared to sickle less readily than uninfected cells, by light microscopy criteria, but electron micrographs demonstrated the presence of polymerized deoxyhemoglobin S with a high frequency. It is concluded that enhanced sickling of plasmodium-infected AS cells may be one mechanism whereby the hemoglobin S polymorphism is balanced in favor of the heterozygote.
Oxford Nanopore Technology (ONT) direct RNA sequencing enables the sequencing of native RNA molecules without cDNA conversion. The long-read approach captures full-length reads spanning entire genes and has transformed the study of gene expression in Plasmodium parasites by enabling analysis of untranslated regions, isoforms, and alternative splicing. In addition, ONT provides unique insights into non-coding RNAs, RNA modifications, and polyadenylated tail dynamics, which are expanding our understanding of post-transcriptional regulation in Plasmodium, including processes beyond translational repression in gametocytes and sporozoites. Here, we discuss the past and future applications of direct RNA sequencing in Plasmodium research and highlight its advantages, limitations, and future prospects.
In an attempt to generate large numbers of mice resistant to Plasmodium berghei and Babesia rodhaini to be used as donors of antibody-secreting cells for hybridoma production, various methods of inducing resistance to repeated challenge with infected blood cells have been explored. Although results of independent experiments varied markedly, prior injection of CBA/M mice with BCG, and prior infection of BALB/c mice with Plasmodium yoelii, were found to be manipulations capable of inducing resistance to P. berghei. A single dose of serum, harvested from resistant mice challenged several times with P. berghei, could transfer resistance against P. berghei to a proportion of naive CBA/H recipients. Although resistance to multiple B. rodhaini challenge could be induced in mice, in no situation was a host protective effect of a single high dose of serum demonstrated in naive recipients.
Oxythiamine, a thiamine analogue, inhibits Plasmodium falciparum proliferation by acting as an antimetabolite of vitamin B1. To elucidate in more detail its underlying mechanism of action, in vitro drug pressure was employed to generate oxythiamine-resistant P. falciparum lines. Whole-genome sequencing revealed that resistance was conferred by a single-point mutation in the thiamine pyrophosphokinase (TPK) gene. The mutated TPK has reduced activity, thereby likely limiting the conversion of oxythiamine into its active toxic form. To investigate the functional role of TPK across the parasite life cycle, a TPK-knockout line was generated in Plasmodium berghei. TPK-knockout parasites displayed a minor fitness cost during intraerythrocytic proliferation that could be overcome by infecting reticulocytes, but their sensitivity to oxythiamine was reduced fivefold in vivo, consistent with the hypothesis that activation of oxythiamine via TPK is essential for its antiplasmodial activity. In the Anopheles vector, TPK-knockout parasites produced a similar number of oocysts as wild-type parasites, but oocyst maturation was impaired and sporozoite formation was completely inhibited. These findings underscore an essential role for TPK in mediating the antiplasmodial activity of oxythiamine and reveal its critical function in sporogony within the mosquito, supporting its potential as a transmission-blocking target for antimalarial intervention.
BACKGROUND: Artemisinin-based combination therapies are the frontline drugs for the treatment of malaria infections, but, for Plasmodium falciparum, the efficacy of artemisinin is threatened by the spread of resistance. Plasmodium vivax is the second most common cause of human malaria, but there is little information on its susceptibility to artemisinin due to the lack of an in-vitro culture system. This study aims to characterise the response of P vivax to artesunate using clinical, genomic, and transcriptomic data from infected individuals in Cambodia. METHODS: We analysed 161 P vivax infections from 87 patients (six female and 81 male; median age 20 years [IQR 17-26]) enrolled between Nov 10, 2021, and Nov 18, 2022, in a drug efficacy study in Cambodia and treated with 2 mg/kg/day of artesunate for 7 days. To determine clearance rates, we measured parasitaemia before, and 1 h, 2 h, 4 h, 8 h, and 16 h after the first dose of artesunate, and then at 24-h intervals during the 7 days of artesunate therapy. We also examined the parasites' genome sequences and used RNA sequencing of 31 infections to analyse changes in parasite gene expression upon treatment. FINDINGS: All infections were successfully cleared by day 3. However, 49 of the infections displayed a slow clearance after treatment, including nine (6%) infections with a parasite clearance slope half-life greater than 5 h. We observed no significant association between slow clearance and either patient or infection characteristics (including the infection's stage composition). Analyses of gene expression showed that, while fast-clearing parasites displayed significant changes in gene expression immediately upon treatment, slow-clearing parasites had a delayed gene expression response characterised notably by a downregulation of genes associated with haemoglobin endocytosis and digestion. INTERPRETATION: Some Cambodian P vivax parasites clear slowly after artesunate treatment, possibly due to a downregulation of haemoglobin metabolism that might reduce the efficiency of the artesunate. The slow clearance could allow parasites to outlast artesunate treatment and facilitate emergence of resistance to the artemisinin-combination therapy partner drug, threatening malaria elimination effort. FUNDING: US National Institutes of Health.
Saurian malaria species which produce schizonts smaller than normal erythrocyte nuclei, with 4-8 merozoietes and gametocytes equal to or smaller than erythrocyte nuclei in size, parasitizing hosts of the lizard families Scincidae, Iguanidae and Teiidae in the Neotropics are considered to be Plasmodium minasense Carini and Rudolph, 1912. Subspecific designations are given to distinctive populations parasitizing different host species: P. minasense minasense is recognized from the type host, Mabuya mabouya of Brasil; P. minasense carinii Leger and Mouzels, 1917 from Iguana iguana of coastal South America; P. minasense anolisi subsp. nov. from Anolis limifrons of Panama; P. minasense capitoi subsp. nov. from Anolis capito of Panama; P. minasense plicae subsp. nov. from Plica umbra of Guyana; P. minasense tegui subsp. nov. from Tupinambis teguixin of Venezuela; and P. minasense diminutivum Telford, 1973, new combination, from Ameiva ameiva of Panama. Plasmodium rhadinurum Thompson and Huff, 1944 is recognized as a distinct species at present on the basis of possessing schizonts of different shape, asexual stages with filamentous projections in most portions of its range, and larger gametocytes, as well as apparent sympatry with P. minasense carinii in some areas.
The ability of concanavalin A to bind erythrocytes but not malarial parasites was used for the development of a method of merozoite isolation: cells from infected blood were allowed to bind to a column of concanavalin A linked to Sepharose beads and merozoites naturally released by maturation of the schizonts bound to the gel were collected. The principle of this method allows its application to several Plasmodium species. The kinetics of merozoite production and the quality of the preparations (purity, infectivity, and ultrastructural morphology) were investigated by using Plasmodium chabaudi.