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Plasmodium inui (Halberstaedter and von Prowazek, 1907), a malarial parasite of Old World monkeys that occurs in isolated pockets throughout the Celebes, Indonesia, Malaysia, and the Philippines, has traditionally been considered to be related more closely to Plasmodium malariae of humans (and its primate counterpart Plasmodium brasilianum), than to other primate Plasmodium species. This inference was made in part because of the similarities in the periodicities or duration of the asexual cycle in the blood, the extended sporogonic cycle, and the longer period of time for development of the pre-erythrocytic stages in the liver. Both P. inui and P. malariae have quartan (72 hr) periodicities associated with their asexual cycle, whereas other primate malarias, such as Plasmodium fragile and Plasmodium cynomolgi, are associated with tertian periodicities (48 hr), and Plasmodiumn knowlesi, with a quotidian (24 hr) periodicity. Phylogenetic analyses of portions of orthologous small subunit ribosomal genes reveal that P. inui is actually more closely related to the Plasmodium species of the "vivax-type" lineage than to P. malariae. Ribosomal sequence analysis of many different, geographically isolated, antigenically distinct P. inui isolates reveals that the isolates are nearly identical in sequence and thus members of the same species.
In order to determine the reliability of two commercial tests for the rapid detection of plasmodial antigen in cases of infection with Plasmodium ovale and Plasmodium malariae, the products were evaluated in four centers and a search of the relevant literature was performed. The results of the present and previous studies were compared. With overall sensitivities ranging between 18.8% and 47.6% for Plasmodium malariae and between 20% and 31.3% for Plasmodium ovale, it is evident that neither test is reliable for the detection of Plasmodium ovale and Plasmodium malariae infections.
Eight species of Anopheles mosquitoes from indoor/outdoor human landing collections in Belize, Central America, were examined for human Plasmodium circumsporozoite protein (CSP) using an enzyme-linked immunosorbent assay (ELISA). A total of 14 of 9,104 females tested were positive from general surveys throughout Belize and three of 11,966 were positive from a longitudinal study in Caledonia, northern Belize. ELISA results, using pooled head-thorax preparations and species-specific monoclonal antibodies directed against the circumsporozoite proteins of Plasmodium falciparum and two Plasmodium vivax polymorphs (210 and VK247), found four species reactive: Anopheles vestitipennis (3 pools), Anopheles darlingi (2 pools), Anopheles albimanus (10 pools), and Anopheles gabaldoni (2 pools). The minimum field infection rates (MFIR) for combined Plasmodium species from the general survey were 0.282% for An. vestitipennis, 0.271% for An. darlingi, 0.126% for An. albimanus, and 0.395% for An. gabaldoni. MFIRs for combined Plasmodium species from the longitudinal study in the village of Caledonia were 0.018% for both An. vestitipennis and An. albimanus and 1.66% for An. gabaldoni. Positive CSP pools were collected from the Cayo, Corozal, Orange Walk, Stann Creek, and Toledo political districts. No CSP positive pools were detected from collections in the Belize District. The study provides valuable information on the spatial distribution and species type of Plasmodium positive mosquitoes. This information, in combination with other vector data, suggest that An. vestitipennis and An. darlingi are commonly involved in malaria transmission. Additionally, these species appear to be much more efficient vectors than An. albimanus in Belize.
Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface. Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus, is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.
We produced a hybridoma secreting an immunoglobulin G1 monoclonal antibody against the circumsporozoite protein of the human malaria parasite Plasmodium malariae (Uganda 1/CDC). The monoclonal antibody produces a circumsporozoite precipitation reaction when incubated with viable sporozoites of P. malariae and reacts at high titers with heat-fixed sporozoites in an indirect immunofluorescent antibody test. Using the purified monoclonal antibody and Western blot analysis, we identified two polypeptides with apparent molecular weights of 60,000 (Pm 60) and 48,000 (Pm 48) in extracts of P. malariae sporozoites. Two-dimensional electrophoretic analysis of Pm 60 and the circumsporozoite protein Pm 48 indicated their isoelectric points to be acidic, with values of 5.3 and 4.7 to 5.0, respectively. A two-site immunoradiometric assay showed that the circumsporozoite protein recognized by the monoclonal antibody contains a repetitive epitope. P. malariae monoclonal antibody also reacted strongly with sporozoites of the simian parasite Plasmodium brasilianum, indicating a shared epitope on sporozoites of the two species. The P. malariae antibody did not bind sporozoite antigens of any other primate malarias, including Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale.
The splenectomy of a female Lemur macaco macaco, showing a scanty blood infection by Haemosporidians and a Trypanosome was followed by a dramatic increase of the rate of intra-erythrocytic parasitaemia. Three species of Plasmodium where then identified. The first species was unknown; it is described in this paper and named Plasmodium coulangesi n. sp. It is characterised by--the low (6). constant number of merozoites in mature schizonts,--the disposition of the pigment, well apart from the parasitic mass to which it is linked by a tiny wisp of cytoplasm,--the normal host erythrocyte, the shape, size and colour of which are unaltered. The second species was provisionaly designated as Plasmodium sp.; it was previously seen in the same host by Garnham and Uilenberg in 1975 and designated by these authors as Plasmodium girardi Buck, Coudurier et Quesnel, 1952. Only gametocytes of the last species were found; they are similar to those of Plasmodium lemuris Huff and Hoogstraal, 1963.
The morphology and enzyme forms of malaria parasites isolated from 50 wild caught specimens of Thamnomys rutilans from the Central African Republic have been studied and three distinct species of Plasmodium identified. One species has been confirmed as Plasmodium yoelii yoelii. Morphological features of both the remaining species correspond to those given by Landau (1965) in her original description of Plasmodium chabaudi. For one of these species the name P. chabaudi has been retained; the other species, which closely resembles subspecies of Plasmodium vinckei from other regions of Africa, has been designated Plasmodium vinckei petteri subsp. nov. P. chabaudi and P.v. petteri are distinguished from each other both in their morphology in the blood and sporogonic stages, and in their enzyme forms.
The acyclic adenosine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with Plasmodium berghei, increase of parasitaemia can be blocked for 4-6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase alpha-like enzymes of P. falciparum and P. berghei are inhibited with an IC50 = 40 microM and a gamma-like DNA polymerase from P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that Plasmodium DNA polymerases are targets for this class of nucleotide analogue.
As Plasmodium rely extensively on homolactic fermentation for energy production, Plasmodium falciparum lactate dehydrogenase (PfLDH)--the key enzyme in this process--has previously been suggested as a novel target for antimalarials. This enzyme has distinctive kinetic and structural properties that distinguish it from its human homologues. In this study, we now describe the expression, kinetic characterisation and crystal structure determination of the LDH from Plasmodium berghei. This enzyme is seen to have a similar kinetic profile to its P. falciparum counterpart, exhibiting the characteristic lack of substrate inhibition that distinguishes plasmodial from human LDHs. The crystal structure of P. berghei lactate dehydrogenase (PbLDH) shows a very similar active site arrangement to the P. falciparum enzyme. In particular, an insertion of five amino acid residues in the active site loop creates an enlarged volume in the substrate binding site, and characteristic changes in the residues lining the NADH cofactor binding pocket result in displacement of the cofactor relative to its observed position in mammalian and all other LDH structures. These results imply the special features previously described for PfLDH may be shared across the Plasmodium genus, supporting the universal application of therapeutics targeting this enzyme.
The genes encoding merozoite surface protein 4/5 (MSP4/5) from Plasmodium berghei and Plasmodium yoelii have been cloned and completely sequenced. Comparisons of the predicted protein sequences with those of Plasmodium chabaudi MSP4/5 and Plasmodium falciparum MSP4 and MSP5 show general structural similarities. All predicted proteins contain hydrophobic signal sequences, potential GPI attachment sequences and a single epidermal growth factor (EGF)-like domain at the C-terminus. The amino acid sequence of the EGF-like motif is highly conserved in rodent malaria species and also shows a considerable degree of similarity with the EGF-like domains found in the P. falciparum proteins. Both the P. yoelii and P. berghei genes show evidence of both spliced and unspliced mRNA at steady state. This phenomenon is similar to that seen for the P. chabaudi MSP4/5 gene, and is believed to be involved in regulation of protein expression. We describe here the construction of clones expressing full length recombinant protein. Antibodies directed against recombinant MSP4/5 proteins recognize a single polypeptide on parasite material and show crossreactivity between MSP4/5 from different murine malaria species, but do not crossreact with either MSP4 or MSP5 from P. falciparum. The various antisera show reactivity against reduction sensitive epitopes as well as reduction insensitive epitopes.
Synthetic peptides representing conserved MSA-2 sequences are being considered as a possible component of a blood stage malaria vaccine. Antibody response towards the entire N-terminal conserved region of MSA-2 and its constituent B-epitope SNTFINNA following immunisation of BALB/c and C57BL/6 mice with different peptide constructs was assessed by ELISA and immunofluorescence antibody test (IFAT). Co-linear synthesis of SNTFINNA-epitope in tandem with the entire N-terminal conserved region peptide (P23) made this construct, namely P8.P23, to be highly immunogenic in both mouse strains, with the antibody response to the SNTFINNA epitope comparable to that following tetanus toxoid protein conjugate immunisation. The antibodies raised specifically recognised the schizont stages of Plasmodium falciparum and Plasmodium yoelii. There was no protection observed upon challenge of immunised BALB/c and C57BL/6 mice with the highly lethal Plasmodium yoelii nigeriensis strain. On the contrary, BALB/c mice immunised with P8.P23 construct were able to resist blood stage infection induced by Plasmodium yoelii yoelii 265BY parasites, while animals inoculated with P23 did not control infection. Affinity purified rabbit anti-SNTFINNA IgG showed more than 60% inhibition of merozoite invasion of fresh erythrocytes in in vitro P. falciparum culture. The low prevalence of antibody response to SNTFINNA-epitope, tested in a dot-blot assay, was observed in sera of 80 individuals living in malaria endemic area in a India; the phenomenon may point out the cryptic character of epitopes residing at the N-terminal conserved region of MSA-2.
The epidemiology of malaria in 2 riverine localities in Rondĵnia, Brazilian western Amazĵnia, was assessed by a 1-year study at Portuchuelo, and a cross-sectional survey at riverine communities at Rio Machado (= Ji-Parana). Plasmodium spp. infections were diagnosed by light microscopy and by polymerase chain reaction (PCR) amplification of ribosomal DNA. PCR was 6-7 times more efficient than microscopy for detecting plasmodial infections. Both Plasmodium vivax and Plasmodium falciparum infections occurred as asymptomatic and symptomatic forms of the disease. The relation between symptomatic and asymptomatic clinical forms was roughly similar for both species of Plasmodium. Symptomless patients were monitored for 2 months. The prevalence of symptomless infections was 4-5 times higher than the symptomatic ones--respectively, 20% and 4.6% for Portuchuelo and 49.5% and 10% for Ji-Parana. Symptomatic malaria occurred mostly in patients in younger age groups. In contrast, there was a significant association of symptomless malaria with older age groups (medians of 26.5 and 21 years, respectively, for Portuchuelo and Ji-Parana), whereas the age medians for symptomatic malaria were 14 and 8 years, respectively, in the 2 regions. Symptomatic malaria also was more prevalent in groups living for shorter times in Amazĵnia (13 and 4 years, respectively, for Portuchuelo and Ji-ParanA) as compared with symptomless malaria, which was more prevalent in groups living for longer periods in the region (medians of 25.5 and 18 years, respectively, for Portuchuelo and Ji-Paraná). The high prevalence of symptomless malaria may pose new problems for the currently adopted strategy for the control of malaria in the Amazonian region, which is essentially based on the treatment of symptomatic patients.
Sera of Gambian individuals and rhesus monkeys immune against infections with Plasmodium falciparum and plasmodium knowlesi, respectively, were reacted with triton X-100-solubilized membranes of infected erythrocytes. Indirect immune precipitation with Staphylococcus aureus, Cowan strain A, followed by dodecylsulfate-polyacrylamide gel electrophoresis, were used to identify interspecies plasmodial antigens that were immunogenic in vivo. Both types of sera specifically precipitated Plasmodium-specific antigens with Mrs of 125,000, 90,000, and 65,000 to 50,000 from membranes of P. knowlesi-infected erythrocytes that had been labeled with 125I using the lactoperoxidase-catalyzed radioiodination or metabolically with 14C-amino acids. In addition, P. falciparum inhibited the precipitation of P. knowlesi antigens by the Gambian immune sera. Our results indicate, that during erythrocytic schizogony, interspecies Plasmodium antigens are exposed on the surfaces of infected erythrocytes.
GTP cyclohydrolase (EC 3.5.4.16), the first enzyme in the pteridine pathway leading to the de novo formation of folic acid, has been identified and isolated from the human malaria parasite, Plasmodium falciparum. The enzyme was purified 200-fold by high performance size-exclusion chromatography on a TSK-G-3000 SW protein column. The molecular weight was estimated at 300 000. Optimal enzyme activity was observed at pH 8.0 and 42 degrees C. The Km for GTP was 54.6 microM. Products of the enzyme reaction were identified as the carbon-8 of GTP and D-erythro-dihydroneopterin triphosphate. ATP was a competitive inhibitor (Ki = 600 microM) of the enzyme. Activity of the enzyme was Mg2+-independent, whereas Mn2+, Cu2+ and Hg2+ (5 mM) were inhibitory. GTP cyclohydrolase activity was also identified in a murine parasite, Plasmodium berghei, and a simian parasite, Plasmodium knowlesi. Activity of the enzyme in P. knowlesi, an intrinsically synchronous quotidian parasite, was found to be dependent on the stage of parasite development.
Irradiated sporozoites are generally thought to elicit protective immune responses that are parasite stage and species specific. But immunization with Plasmodium falciparum sporozoites delivered by the bite of infected mosquitoes protects an average of 60% mice from Plasmodium berghei sporozoite infection. Protection appears to be specific as P. falciparum sporozoite-immunized mice protected against P. berghei remain susceptible to Plasmodium yoelii sporozoite infection. Passively transferred immunoglobulin from P. falciparum sporozoite-immunized mouse serum protected naive mice against challenge with P. berghei sporozoites, indicating that cross-protection is mediated, at least in part, by anti-sporozoite antibody. Antibody-mediated protection may not be due to cross-reaction between P. falciparum and P. berghei CS proteins because mice immunized with the recombinant P. falciparum CS protein repeat vaccine candidate, R32tet32, remain susceptible to P. berghei sporozoite infection.
Cytosoluble 100,000 X g extracts from Plasmodium berghei or Plasmodium falciparum infected red blood cells were shown to hydrolyze erythrocyte spectrin. By Fast Protein Liquid Chromatography (FPLC), these enzymes were purified and exhibited a pI of 4.5 and Mr of 37,000 using SDS-PAGE under reducing conditions. An immunochemical enzyme assay using anti-spectrin antibodies was developed. The optimal activity using spectrin as substrate was at pH 5.0, and the enzymes were strongly inhibited by HgCl2, ZnCl2, chymostatin, leupeptin and aprotinin, and moderately by pepstatin. These properties of the Pf37 and Pb37 proteases differ from the Plasmodium lophurae and P. falciparum 'cathepsin D-like' enzymes and from the serine or cysteine neutral proteases previously described in P. falciparum and P. berghei infected red blood cells. While the Pf37 and Pb37 enzymes cleaved spectrin preferentially, degradation of band 4.1 was also observed with high concentration of enzyme. The parasite origin of the Pf37 protease was clearly demonstrated, since purified radiolabeled enzyme was active on spectrin. A high-molecular-weight polymer (greater than 240 kDa) was often observed on incubating purified spectrin and Pf37 protease. The breakdown of erythrocyte cytoskeletal components could be of interest in the release of merozoites from segmented schizonts or during the process of invasion of erythrocytes by merozoites.