Vaccination with live Plasmodium yoelii blood stage parasites under chloroquine cover induces cross-stage immunity against malaria liver stage.
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ABSTRACT:
SUBMITTER: Belnoue E
PROVIDER: S-EPMC5551044 | biostudies-other | 2008 Dec
REPOSITORIES: biostudies-other
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Project description:In our work, we aim to develop a malaria vaccine with cross-strain (-species) protection. C57BL/6 mice infected with the P. berghei ANKA strain (PbA) develop experimental cerebral malaria (ECM). In contrast, ECM development is inhibited in infected mice depleted of T cells. The clinical applications of immune-cell depletion are limited due to the benefits of host defense against infectious diseases. Therefore, in the present study we attempted to develop a new method for preventing ECM without immune cell depletion. We demonstrated that mice inoculated with a heterologous live-vaccine of P. yoelii 17XNL were able to prevent both ECM and lung pathology and survived longer than control mice when challenged with PbA. Live vaccination protected blood-organ barriers from PbA infection. Meanwhile, live vaccination conferred sterile protection against homologous challenge with the P. yoelii 17XL virulent strain for the long-term. Analysis of the immune response induced by live vaccination showed that cross-reactive antibodies against PbA antigens were generated. IL-10, which has an immunosuppressive effect, was strongly induced in mice challenged with PbA, unlike the pro-inflammatory cytokine IFNγ. These results suggest that the protective effect of heterologous live vaccination against ECM development results from IL-10-mediated host protection.
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Project description:The purpose of this research is to identify and evaluate the global gene expression of the rodent malaria parasites Plasmodium yoelii, Plasmodium berghei and Plasmodium chabaudi blood-stage parasites and specifically compare the blood stage gene expression profiles of samples derived from previous studies on Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi
2016-04-08 | GSE80015 | GEO
Project description:Understanding protective immunity to malaria is essential for the design of an effective vaccine to prevent the large number of infections and deaths caused by this parasitic disease. To date, whole-parasite immunization with attenuated parasites is the most effective method to confer sterile protection against malaria infection in clinical trials. Mouse model studies have highlighted the essential role that CD8(+) T cells play in protection against preerythrocytic stages of malaria; however, there is mounting evidence that antibodies are also important in these stages. Here, we show that experimental immunization of mice with Plasmodium yoelii fabb/f(-) (Pyfabb/f(-)), a genetically attenuated rodent malaria parasite that arrests late in the liver stage, induced functional antibodies that inhibited hepatocyte invasion in vitro and reduced liver-stage burden in vivo. These antibodies were sufficient to induce sterile protection from challenge by P. yoelii sporozoites in the absence of T cells in 50% of mice when sporozoites were administered by mosquito bite but not when they were administered by intravenous injection. Moreover, among mice challenged by mosquito bite, a higher proportion of BALB/c mice than C57BL/6 mice developed sterile protection (62.5% and 37.5%, respectively). Analysis of the antibody isotypes induced by immunization with Pyfabb/f(-) showed that, overall, BALB/c mice developed an IgG1-biased response, whereas C57BL/6 mice developed an IgG2b/c-biased response. Our data demonstrate for the first time that antibodies induced by experimental immunization of mice with a genetically attenuated rodent parasite play a protective role during the preerythrocytic stages of malaria. Furthermore, they highlight the importance of considering both the route of challenge and the genetic background of the mouse strains used when interpreting vaccine efficacy studies in animal models of malaria infection.
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Project description:Microarray studies using synchronized Plasmodium falciparum parasites have revealed a ‘continuous cascade’ of gene expression. Reports vary regarding the stability in these transcriptional patterns in the presence of external stressors. Using Plasmodium yoelii 17X parasites replicating in vivo, we have examined differential gene expression in parasites isolated from individual mice, from independent infections, during ascending and peak parasitemia and in the presence and absence of host antibody responses. Across experimental conditions, transcription was surprisingly stable. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability; however, even these changes were modest. Of genes that were differentially expressed, many are of unknown function. There was little to no differential expression of members of the yir and pyst-a multigene families, although a relatively large number of these were expressed during blood-stage infection regardless of experimental condition. Taken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment and 2) concurrent expression of a large number of the yir and pyst-a genes may function to divert host immune responses away from invariant protective antigens.
2011-11-01 | GSE31274 | GEO
Project description:Microarray studies using synchronized Plasmodium falciparum parasites have revealed a ‘continuous cascade’ of gene expression. Reports vary regarding the stability in these transcriptional patterns in the presence of external stressors. Using Plasmodium yoelii 17X parasites replicating in vivo, we have examined differential gene expression in parasites isolated from individual mice, from independent infections, during ascending and peak parasitemia and in the presence and absence of host antibody responses. Across experimental conditions, transcription was surprisingly stable. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability; however, even these changes were modest. Of genes that were differentially expressed, many are of unknown function. There was little to no differential expression of members of the yir and pyst-a multigene families, although a relatively large number of these were expressed during blood-stage infection regardless of experimental condition. Taken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment and 2) concurrent expression of a large number of the yir and pyst-a genes may function to divert host immune responses away from invariant protective antigens. 1. P. yoelii 17X gene expression profiles were determined in blood-stage parasites isolated from infected Balb/c mice (male, 8-12 weeks old) as follows: a. Mouse 1 (M1), Mouse 2 (M2), Mouse 3 (M3), Donor (D) mouse – three mice simultaneously infected with P. yoelii 17X iRBCs from a single donor mouse. Parasite RNA was isolated early during infection when parasitemia was ascending as follows: M1 - day 11 at 13.0% parasitemia; M2 - day 10 at 11.1% parasitemia; M3 - day 10 at 18.6% parasitemia; D – day 11 at 18.7% parasitemia. b. Infection #1 (I1), infection #2 (I2), infection #3 (I3), infection #4 (I4) – four groups of mice infected on four separate occasions using P. yoelii 17X iRBCs obtained from four separate donor mice. In each case, P. yoelii 17X RNA was isolated from iRBCs obtained on days 10-11 of infection when parasitemia was ascending and was ~15%. c. Day 10 (D10), Day 14 (D14) – P. yoelii 17X RNA isolated from iRBCs during infection #2 on day 10 (14% parasitemia, 14.4% reticulocytes) and on day 14 of infection #2 (43.5% parasitemia, 57.9% reticulocytes). d. WT and JHD - P. yoelii 17X RNA isolated from iRBCs during infection #4 from immunologically intact, wild-type Balb/c mice and B cell deficient, JHD mice on a Balb/c background (ascending infection, 15% parasitemia). e. QA and RMP - P. yoelii 17X RNA isolated from iRBCs during infection #1 from mice previously immunized with a preparation of membrane proteins isolated from P. yoelii 17X infected reticulocytes (PyRMP) (day 12, 13.3% parasitemia and Quil A immunized (QA) control mice (day 10, 15.6% parasitemia) 2. On each array, gene expression in P. yoelii 17X blood-stage parasites was evaluated relative to a standard comparator of purified P. yoelii 17XL total RNA (pooled RNA from 45 mice, mean parasitemia ~35%). Each sample was analyzed on three replicate arrays, one of which was a standard dye-flip. One exception was the infection #3 sample which was analyzed on only on two arrays. On each array, oligonucleotides were spotted in duplicate. 3. Through the use of the standard reference RNA, the following 15 pairwise comparisons across samples were made: (M1 vs M2); (M2 vs M3); (M1 vs M3); (D vs M1); (D vs M2); (D vs M3); (I1 vs I2); (I1 vs I3); (I1 vs I4); (I2 vs I3); (I2 vs I4); (I3 vs I4); (D10 vs D14); (WT vs JHD); (QA vs RMP)
2011-11-01 | E-GEOD-31274 | biostudies-arrayexpress
Project description:Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.
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Project description:BackgroundPlasmodium has a complex cell biology and it is essential to dissect the cell-signalling pathways underlying its survival within the host.MethodsUsing the fluorescence resonance energy transfer (FRET) peptide substrate Abz-AIKFFARQ-EDDnp and Fluo4/AM, the effects of extracellular ATP on triggering proteolysis and Ca²⁺ signalling in Plasmodium berghei and Plasmodium yoelii malaria parasites were investigated.ResultsThe protease activity was blocked in the presence of the purinergic receptor blockers suramin (50 μM) and PPADS (50 μM) or the extracellular and intracellular calcium chelators EGTA (5 mM) and BAPTA/AM (25, 100, 200 and 500 μM), respectively for P. yoelii and P. berghei. Addition of ATP (50, 70, 200 and 250 μM) to isolated parasites previously loaded with Fluo4/AM in a Ca²⁺-containing medium led to an increase in cytosolic calcium. This rise was blocked by pre-incubating the parasites with either purinergic antagonists PPADS (50 μM), TNP-ATP (50 μM) or the purinergic blockers KN-62 (10 μM) and Ip5I (10 μM). Incubating P. berghei infected cells with KN-62 (200 μM) resulted in a changed profile of merozoite surface protein 1 (MSP1) processing as revealed by western blot assays. Moreover incubating P. berghei for 17 h with KN-62 (10 μM) led to an increase in rings forms (82% ± 4, n = 11) and a decrease in trophozoite forms (18% ± 4, n = 11).ConclusionsThe data clearly show that purinergic signalling modulates P. berghei protease(s) activity and that MSP1 is one target in this pathway.
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Project description:The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4(+) and CD8(+) T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4(+) T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8(+) T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8(+) T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4(+) and CD8(+) T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.
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Project description:In endemic areas with high transmission intensities, malaria infections are very often composed of multiple genetically distinct strains of malaria parasites. It has been hypothesised that this leads to intra-host competition, in which parasite strains compete for resources such as space and nutrients. This competition may have repercussions for the host, the parasite, and the vector in terms of disease severity, vector fitness, and parasite transmission potential and fitness. It has also been argued that within-host competition could lead to selection for more virulent parasites. Here we use the rodent malaria parasite Plasmodium yoelii to assess the consequences of mixed strain infections on disease severity and parasite fitness. Three isogenic strains with dramatically different growth rates (and hence virulence) were maintained in mice in single infections or in mixed strain infections with a genetically distinct strain. We compared the virulence (defined as harm to the mammalian host) of mixed strain infections with that of single infections, and assessed whether competition impacted on parasite fitness, assessed by transmission potential. We found that mixed infections were associated with a higher degree of disease severity and a prolonged infection time. In the mixed infections, the strain with the slower growth rate was often responsible for the competitive exclusion of the faster growing strain, presumably through host immune-mediated mechanisms. Importantly, and in contrast to previous work conducted with Plasmodium chabaudi, we found no correlation between parasite virulence and transmission potential to mosquitoes, suggesting that within-host competition would not drive the evolution of parasite virulence in P. yoelii.
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