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Culex nigripalpus experimentally transmitted Plasmodium hermani, a plasmodium of wild turkeys (Meleagris gallopavo) in Florida. The mosquitoes were infected by feeding upon blood induced parasitemias in domestic turkey poults. The resulting sporozoites, transmitted by either mosquito bites or injection, produced malaria infections in domestic poults.
Twenty-three of 310 blood samples taken from live-trapped eastern wild turkeys (Meleagris gallopavo silvestris) from Missouri (USA), and hunter-killed birds from Wisconsin, North Dakota and Minnesota (USA), and inoculated into domestic broad-breasted-white turkey poults were positive for two species of Plasmodium. Twenty-one of the positive samples were infected with P. (Novyella) kempi, and two samples from Wisconsin were infected with P. (Giovannolaia) lophurae. Twenty percent of 310 blood smears were positive for Haemoproteus melagridis, while only 3% were infected with Leucocytozoon smithi. A statistically higher prevalence of Plasmodium spp. from 1983 to 1984 was observed in Wisconsin, and in the samples from Minnesota when compared with both Missouri and Wisconsin. Turkeys from Wisconsin and Minnesota had both a statistically higher prevalence and mean intensity of H. meleagridis than birds from Missouri. Evidence indicates that P. kempi has been introduced into other states along with the vertebrate hosts. It is suggested that greater care should be exercised when translocated wild turkeys are introduced into areas where there are other endangered or threatened avian species.
CD8+ T cells have been implicated as critical effector cells in protection against preerythrocytic stage malaria, including the potent protective immunity of mice and humans induced by immunization with radiation-attenuated Plasmodium spp. sporozoites. This immunity is directed against the Plasmodium spp. parasite developing within the host hepatocyte and for a number of years has been presumed to be mediated directly by CD8+ CTL or indirectly by IFN-gamma released from CD8+ T cells. In this paper, in BALB/c mice, we establish that after immunization with irradiated sporozoites or DNA vaccines parasite-specific CD8+ T cells trigger a novel mechanism of adaptive immunity that is dependent on T cell- and non-T cell-derived cytokines, in particular IFN-gamma and IL-12, and requires NK cells but not CD4+ T cells. The absolute requirement for CD8+ T cells to initiate such an effector mechanism, and the requirement for IL-12 and NK cells in such vaccine-induced protective immunity, are unique and underscore the complexity of the immune responses that protect against malaria and other intracellular pathogens.
Relapse infections are an important obstacle to the successful treatment and control of Plasmodium vivax malaria, but little is known about the nature of the relapse. To provide insight into the antigenic disparity of the parasites causing initial clinical symptoms and causing relapse, a panel of 58 monoclonal antibodies (MAbs) against erythrocytic stages of Plasmodium vivax was tested by indirect fluorescent antibody test in five relapse cases. The initial and relapse strains from three patients (R3, R4, and R5) exhibited similar IFA reactivity with all MAbs tested, whereas the isolates from two relapse cases (R1 and R2) showed different patterns of reactivity and were seen only with 15 MAbs In case R1, different IFA reactivities were observed with 12 MAbs, nine of which reacted with the initial (RPV261) but not the relapse (RPV393) isolates, whereas the other three MAbs reacted only with the relapse isolates. With regards to the second relapse case (R2) in whom two relapses occurred, different IFA reactivities were demonstrated with seven MAbs that reacted only with the initial isolate (RPV 182) and with the isolate from the first relapse (RPV 240) but not with the isolate from the second relapse (RPV 300). The antibody responses from patients who developed primary clinical symptoms and relapse were detected by Western immunoblotting. In cases R3, R4 and R5, there was no difference in the spectrum of antigens from initial and relapse sera recognized by the antibodies. In contrast, in cases R1 and R2, the molecules recognized by antibodies in initial and relapse sera were markedly altered. In case R1, the series of molecules of P. vivax antigens recognized by initial (RPV 261) and relapse (RPV 393) sera were 21, 25, 31, 39, 42, 61, 95, 115, 200, > 200 kDa and 21, 24, 31, 35, 57, 75, 200, > 200 kDa, respectively. In case R2, the initial serum (RPV 182) recognized P. vivax antigens with molecular weights of 23, 30, 52, 57, 68, 75, 85, 95, 115, and 195 kDa while the first relapse (RPV 240) and the second relapse sera recognized P. vivax antigens with molecular weights of 23, 30, 52, 85, 95,115 kDa and 30, 57, 68, 75, 85,195 kDa, respectively.
BACKGROUND: The 19 kDa C-terminal region of the merozoite surface protein 1 (MSP1(19)) has been suggested as candidate for part of a subunit vaccine against malaria. A major concern in vaccine development is the polymorphism observed in different plasmodial strains. The present study examined the extension and immunological relevance of the allelic polymorphism of the MSP1(19) from Plasmodium vivax, a major human malaria parasite. MATERIALS AND METHODS: We cloned and sequenced 88 gene fragments representing the MSP1(19) from 28 Brazilian isolates of P. vivax. Subsequently, we evaluated the reactivity of rabbit polyclonal antibodies, a monoclonal antibody, and a panel of 80 human sera to bacterial and yeast recombinant proteins representing the two allelic forms of P. vivax MSP1(19) described thus far. RESULTS: We observed that DNA sequences encoding MSP1(19) were not as variable as the equivalent region of other species of Plasmodium, being conserved among Brazilian isolates of P. vivax. Also, we found that antibodies are directed mainly to conserved epitopes present in both allelic forms of the protein. CONCLUSIONS: Our findings suggest that the use of MSP1(19) as part of a subunit vaccine against P. vivax might be greatly facilitated by the limited genetic polymorphism and predominant recognition of conserved epitopes by antibodies.
Chloroquine has been the standard treatment for Plasmodium vivax malaria for more than 40 years in most regions of the world. Recently, however, chloroquine-resistant P. vivax has been reported from Oceania, several parts of Asia, and South America. In order to assess the situation in Thailand, 886 patients with vivax malaria who were admitted to the Bangkok Hospital for Tropical Diseases from 1992 to 1997 were followed prospectively. Most of the patients had been infected on the western border of Thailand and were experiencing their first malarial infection when admitted. All received oral chloroquine (approximately 25 mg base/kg body weight, administered over 3 days) and then were randomized to receive primaquine (15 mg daily for 14 days) or no further treatment. All the patients were initially responsive to chloroquine, clearing their parasitaemias within 7 days, and there were no significant differences in the clinical or parasitological responses between those treated with primaquine and those given no further treatment. Plasmodium vivax parasitaemias re-appeared within 28 days of chloroquine treatment in just four patients. In each of these four cases, re-treatment with the same regimen of chloroquine resulted in eradication of the parasitaemia, with no further appearance of parasitaemia during the next, 28-day, follow-up period. These data indicate that virtually all acute (i.e. blood-stage) P. vivax infections acquired in Thailand can still be successfully treated with chloroquine.
We have reported that the human malaria parasite, Plasmodium falciparum, repairs apurinic/apyrimidinic (AP) sites on DNA by a long-patch base excision repair (BER) pathway. This biology is different from that in mammalian cells, which predominantly repair AP sites by a DNA-polymerase-beta-dependent, one-nucleotide patch BER pathway. As a starting point for the identification and biochemical characterization of the enzymes involved in the parasite DNA BER pathway, we chose characterization of the AP endonuclease activity in a P. falciparum cell-free lysate. Evidence is provided for the presence of class II, Mg(2+)-dependent and independent AP endonucleases in the parasite lysate. The investigation of the processing of AP sites in Plasmodium will provide new information about long-patch BER pathways; if they are different from those in the human host they might provide a new target for anti-malarial chemotherapy.
Among the microorganisms that strictly depend upon other organisms (hosts or vectors) for achieving their life cycle, protozoan and metazoan parasites have been often primarily distinguished through the major pathogenic processes they could induce. A variety of different mechanisms linked to parasitism can indeed systemically (e.g. Plasmodium falciparum) or locally (e.g. Toxoplasma gondii) induce important alterations of tissue homeostasis. But more than obvious pathogenicity, it is the capacity to be transmitted that is essential for parasite survival and there is increasing evidence that certain parasites can achieve their life cycle to the point of transmission in the absence of clinically detectable processes. For this, constitutive microenvironments of the host or vector can be exploited. Moreover, parasites are sometimes able to highjack effectors of the host's immune response towards conditioning the microenvironments which are permissive to differentiation of transmissible developmental stages. Based on a few examples taken from studies on the transmission stages of Leishmania, Toxoplasma and Plasmodium, we have here attempted to formulate a few hypothesis on the biology of the transmission stages of P. falciparum, i.e. on gametocytogenesis and sporozoite maturation. As discussants, we may have been somewhat dwarfed by issues evoked by the organizers of this meeting in the title of the session, i.e. 'Vector-parasite-man interactions'!... In reaction, we may have taken refuge in somewhat over-selective comments, biased by the objects of our personal research....
Here are a few sundry reflections and questions stimulated by the talks and discussions in session 3 of the Malariology Centenary Conference 1998 on the 'intimacy' that has been established between Plasmodium and Anopheles. The degree of 'intimacy' achieved in a vectorial system seems to correlate to the difficulties incurred when one attempts to interrupt parasite development in the insect host. The main questions addressed in this essay are as follows: Are antimicrobial peptides the most efficient effector molecules to be used to block sporogonic development of malaria parasites? Are the mosquito defense reactions elicited by Plasmodium invasion deleterious, advantageous or neutral to parasite development? The purpose in asking these questions is to put in perspective the direction of research in this area and to generate new ideas.
Attempts are being made to backcross into Anopheles gambiae s.s. the gene(s) which cause zoophily in Anopheles quadriannulatus. Such a backcrossed strain might be preferable to a Plasmodium-refractory strain as a basis for genetic control because a refractory strain could select for evasion of refractoriness in the wild Plasmodium population. The species composition of the malaria vector population in several Tanzanian villages was overwhelmingly An. gambiae s.s. in a normal rainy season, but consisted of four species, all proved by ELISA and/or PCR to carry P. falciparum sporozoites, at the time of the heavy rains associated with El Niño. Thus any scheme, for malaria transmission control by replacement of vectors by genetically-manipulated non-vectors, would have to be able to replace more than one species.
Trypanosoma musculi brought into Plasmodium berghei-infected mice in the later stages of the malaria infection shows rapid, approximately logarithmic multiplication in the peripheral blood. The trypanosome number increases by a factor of 2-9 per day, multiplication of the parasites kills most mice in a few days. Many multiplicative forms of the trypanosomes and a few trypanosomes without nuclei are seen in blood smears. Histologically and in touch preparations, masses of multiplicative forms of the trypanosomes are seen in the sinusoids of the liver. Aggregates of trypanosomes are found, too, in the kidney medulla and, inconstantly, in venous sinuses of the spleen and postcapillary venules of lymph nodes. Occasionally, trypanosomes may be found extravascularly in the interstitial connective tissue especially of the pancreas, in lymph vessels and lymph node sinuses. - Mice infected in earlier stages of the Plasmodium berghei infection achieve stabilization of trypanosome numbers.
Recombinant fusion protein of cholera toxin B subunit (CTB) and poly-valent protective epitopes of plasmodium falciparum was given to i.m. to C57BL/6j mice and rhesus monkeys three times. In rhesus monkeys, high level of antibodies for CTB (1:6400) and malaria epitopes (1:3200) amtobpdoes were elicited as well as the specific CTL activity for P. plasmodium. After the mice were challenged with sporozoites of P. yeolli, about 50% of them were protected from the patent infection. A blood-stage challenge with 10(8) of P. cynomolgi parasite were given to rhesus monkeys, which showed that two animals in control group were patent infection for at least 30 days, in contrast, the two animals immunized were recovered respectively at the day of 11 and 15 after challenges. The results suggested that cholera toxin acts as an effective adjuvent in the development of malaria vaccine.
Time course of DNase and RNase activities in the sera of random-bred mice infected with Plasmodium malariae (chloroquine-sensitive strain H) was studied. Similarly to viral infection, infection with a protozoa eukaryotic parasite was accompanied by increased DNAse and RNAse activities, though Plasmodium malariae biologically differes from viruses.
Plasmodium falciparum malaria continues to threaten human populations in the tropics and travellers in endemic areas. Drug resistance of the parasite is a major problem in treating this devastating disease. In a prospective trial we investigated the in vitro sensitivity of Plasmodium falciparum to chloroquine, quinine and mefloquine in the Albert Schweitzer Hospital in Lambaréné, Gabon every second year from 1992 to 1998. We used the standard WHO in vitro sensitivity assay. Parasite sensitivity to quinine and mefloquine remained stable over the years. However, parasite resistance to chloroquine decreased highly significantly with the change in local malaria treatment policy. In 1992, 100% of parasite isolates showed resistance to chloroquine, whereas in 1998 only 45% were found resistant.
BACKGROUND: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Reactive oxygen species (ROS) are important mediators of tissue injury during malaria infection. OBJECTIVE: To study the status of hepatic oxidative stress and antioxidant defense indices during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection and poly ICLC treatment of normal and P. y. nigeriensis infected Swiss albino mice. METHODS: Mice were divided into four groups viz., 1. Normal mice, 2. Normal mice treated with poly ICLC (5 mg/kg body weight, i.p.), 3. P. y. nigeriensis infected mice and 4. P. y. nigeriensis infected mice treated with poly ICLC (5 mg/kg body weight, i.p.). RESULTS: P. y. nigeriensis infection caused a significant increase in hepatic oxidative stress indices viz., xanthine oxidase and lipid peroxidation. This was accompanied by a significant increase in antioxidant defense indices viz., reduced glutathione (GSH), glutathione reductase while superoxide dismutase and catalase showed a significant decrease with respect to normal mice. Poly ICLC treatment of P. y. nigeriensis infected mice did not cure blood parasitemia. However, poly ICLC treatment of normal and P. y. nigeriensis resulted in an increased generation of hepatic oxidative stress and an associated increase in the antioxidant defense indices. CONCLUSION: poly ICLC therapy alone is not sufficient to treat the malaria infection caused by multiple drug resistant strain of P. y. nigeriensis. Therefore there is a need to develop newer antimalarias which can act alone or in combination with traditional antimalarials to be effective against drug resistant malarial parasite.
This report summarizes the results of appraisals of various activities of CI-679 (a 2,4-diamino-6-amino-substituted quinazoline) in rhesus monkeys infected with the Ro and Ro/PM strains of Plasmodium cynomolgi. In subjects inoculated with sporozoites, CI-679, administered in appropriate schedules in doses up to and including the maximum tolerated level, neither prevented development of infections with these strains nor cured those already established. Although these evaluations showed that CI-679 was devoid of activity against both early and late tissue schizonts, they indicated that this compound had significant blood schizonticidal activity and suggested that such activity was much greater in infections with the Ro strain than in those with the Ro/PM strain. This latter suggestion, contrary to results of earlier experiments in mice infected with Plasmodium berghei, led to studies of the activities of CI-679 in trophozoite-induced infections. These showed that the total course dose of CI-679 required for cure of previously untreated infections with the Ro/PM strain was tenfold that required for cure of comparable infections with the Ro strain. They also showed that infections with either strain, treated previously with subcurative doses, were often not cured by doses of CI-679 that eradicated previously untreated infections regularly. Subsequent studies showed that emergency of parasites resistant to CI-679 was responsible for these retreatment failures and that this resistance was retained through mosquito transfer.
BACKGROUND: Plasmodium falciparum merozoites bind to and invade human erythrocytes via specific erythrocyte receptors. This establishes the erythrocytic stage of the parasite life cycle that causes clinical disease resulting in 2-3 million deaths per year. We tested the hypothesis that a Plasmodium falciparum ligand, EBA-175 region II (RII), which binds its erythrocyte receptor glycophorin A during invasion, can be used as an immunogen to induce antibodies that block the binding of RII to erythrocytes and thereby inhibit parasite invasion of erythrocytes. Accordingly, we immunized mice, rabbits, and monkeys with DNA plasmids that encoded the 616 amino acid RII. MATERIALS AND METHODS: DNA vaccine plasmids that targeted the secretion of recombinant RII protein with and without the universal T-cell helper epitopes P2P30 were used to immunize mice, rabbits, and Aotus monkeys. RII specific antibodies were assessed by IFA, ELISA, blocking of native [35S] labeled EBA-175 binding to human erythrocytes, and growth inhibition assays, all in vitro. RESULTS: The RII DNA plasmids were highly immunogenic as measured by ELISA and IFA. The anti-RII antibodies blocked the binding of native EBA-175 to erythrocytes, and rosetting of erythrocytes on COS-7 cells expressing RII. Most important, murine and rabbit anti-RII antibodies inhibited the invasion of merozoites into erythrocytes. We immunized nonhuman primates and showed that the RII-DNA plasmids were immunogenic and well tolerated in these monkeys. Monkeys were challenged with parasitized erythrocytes; one of three monkeys that received RII DNA plasmid was protected from fulminant disease. After challenge with live parasites, anti-RII antibody titers were boosted in the immunized monkeys. CONCLUSIONS: By proving the hypothesis that anti-RII antibodies can block merozoite invasion of erythrocytes, these studies pave the way for the clinical evaluation of EBA-175 as a receptor-blockade vaccine.
OBJECTIVE: To approve a theoretical basis for the molecular pathogenesis of human cerebral malaria and treatment with prevention. METHODS: The blood samples were collected from 24 patients with cerebral malaria, 143 with falciparum malaria, 34 with vivax malaria and 20 healthy controls from the endemic areas of Yunnan Province, China. Using the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) technique, we determined the molecular mass (Mr) of these Plasmodium falciparum (P. falciparum) erythrocyte membrane protein 1 (PfEMP1) molecules. RESULTS: Our findings indicate that higher molecular mass (260 kDa-320 kDa) forms of PfEMP1 were expressed on parasitized erythrocyte (PE) from human cerebral malaria patients. Compared with PfEMP1 expressed on PE from human cerebral malaria patients, the expression of PfEMP1 and Plasmodium vivax (P. vivax) erythrocyte membrane protein 1 (PvEMP1) on PE from falciparum malaria patients and vivax malaria patients did not have multiple bands of PfEMP1 of > or = 260 kDa, but had a PfEMP1 with molecular mass of 240 kDa and a PvEMP1 with molecular mass of 180 kDa band separately. Healthy controls expressed an EMP of molecular mass of 140 kDa. CONCLUSION: Results confirm the antigenic variation of higher molecular mass of PfEMP1 whose molecular mass is equal to or exceeds 260 kDa-320 kDa on PE of patients with cerebral malaria. Our results show that the binding of large antigenic variability PfEMP1 molecular mass of 260 kDa-320 kDa on PE from human cerebral malaria patients with diverse receptor molecules on the endothelial cell (EC) of the cerebral microvessels may be involved in the molecular pathogenesis of cerebral malaria.