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Acta Tropica Jul 2016Individuals in natural populations may be infected with multiple different parasites at a time. These parasites may interact with each other or act independently in the...
Individuals in natural populations may be infected with multiple different parasites at a time. These parasites may interact with each other or act independently in the host, and this may result to varying outcomes on host health and survival. This study therefore aimed at investigating the health impact of co-infection of mice with Plasmodium berghei and Trypanosoma brucei. Forty Swiss albino mice (14-17g) were divided into four groups of ten. Mice in groups A and B received 10(6)P. berghei and groups B and C 10(5)T. brucei, while group D were uninfected. The co-infected mice had higher P. berghei and T. brucei parasitaemia, compared with the mono-infected mice. The co-infected mice had significantly (p<0.05) lower survival rate compared with the mono-infected mice. Co-infection of mice with P. berghei and T. brucei resulted in rapid P. berghei and T. brucei development and increased parasitaemia. The leukocyte numbers significantly (p<0.05) reduced on days 12 and 15 post infection among P. berghei infected mice, in the presence or absence of T. brucei. Anaemia and hypoglycaemia was more severe in the co-infected mice. Therefore, co-infection of mice with P. berghei and T. brucei may increase pathologic impact to the host by increasing parasitaemia.
Topics: Animals; Coinfection; Malaria; Mice; Parasitemia; Plasmodium berghei; Survival Rate; Trypanosoma brucei brucei; Trypanosomiasis
PubMed: 27021269
DOI: 10.1016/j.actatropica.2016.03.030 -
Trends in Parasitology Feb 2023The liver is a major entry point and gatekeeper for invasive pathogens. However, high-resolution, spatiotemporal transcriptomic analysis of host-pathogen interactions...
The liver is a major entry point and gatekeeper for invasive pathogens. However, high-resolution, spatiotemporal transcriptomic analysis of host-pathogen interactions has remained challenging. Afriat et al. have deconvoluted Plasmodium berghei liver-stage maturation at an unprecedented scale and discovered molecular signatures of heterogeneity during pre-erythrocytic development of malarial parasites.
Topics: Humans; Liver; Malaria; Liver Diseases; Plasmodium berghei; Communicable Diseases
PubMed: 36567188
DOI: 10.1016/j.pt.2022.12.005 -
Proceedings of the National Academy of... Mar 2018Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by parasites that is associated with high rates of mortality and morbidity....
Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in parasites. Rocaglates are a class of natural products derived from plants of the genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with (CM) and (blood-stage malaria), and can also block replication of different clinical isolates of in human erythrocytes infected ex vivo including drug-resistant isolates. In vivo, a single dosing of CR-1-31B in -infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in -infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.
Topics: Aglaia; Animals; Antimalarials; Disease Models, Animal; Erythrocytes; Eukaryotic Initiation Factor-4F; Female; Humans; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Plant Extracts; Plasmodium berghei; Plasmodium falciparum; Protozoan Proteins
PubMed: 29463745
DOI: 10.1073/pnas.1713000115 -
Scientific Reports Oct 2018Malaria parasite genomes have a range of codon biases, with Plasmodium falciparum one of the most AT-biased genomes known. We examined the make up of synonymous coding... (Comparative Study)
Comparative Study
Malaria parasite genomes have a range of codon biases, with Plasmodium falciparum one of the most AT-biased genomes known. We examined the make up of synonymous coding sites and stop codons in the core genomes of representative malaria parasites, showing first that local DNA context influences codon bias similarly across P. falciparum, P. vivax and P. berghei, with suppression of CpG dinucleotides and enhancement of CpC dinucleotides, both within and aross codons. Intense asexual phase gene expression in P. falciparum and P. berghei is associated with increased A3:G3 bias but reduced T3:C3 bias at 2-fold sites, consistent with adaptation of codons to tRNA pools and avoidance of wobble tRNA interactions that potentially slow down translation. In highly expressed genes, the A3:G3 ratio can exceed 30-fold while the T3:C3 ratio can be less than 1, according to the encoded amino acid and subsequent base. Lysine codons (AAA/G) show distinctive behaviour with substantially reduced A3:G3 bias in highly expressed genes, perhaps because of selection against frameshifting when the AAA codon is followed by another adenine. Intense expression is also associated with a strong bias towards TAA stop codons (found in 94% and 89% of highly expressed P. falciparum and P. berghei genes respectively) and a proportional rise in the TAAA stop 'tetranucleotide'. The presence of these expression-linked effects in the relatively AT-rich malaria parasite species adds weight to the suggestion that AT-richness in the Plasmodium genus might be a fitness adaptation. Potential explanations for the relative lack of codon bias in P. vivax include the distinct features of its lifecycle and its effective population size over evolutionary time.
Topics: Amino Acids; Base Composition; Base Pairing; Codon; DNA, Protozoan; Gene Expression Regulation, Developmental; Genes, Protozoan; Genetic Code; Mutation; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; RNA, Protozoan; RNA, Transfer; Selection, Genetic
PubMed: 30374097
DOI: 10.1038/s41598-018-34404-9 -
Vaccine Dec 2023Long-term protection against malaria remains one of the greatest challenges of vaccination against this deadly parasitic disease. Whole-sporozoite (WSp) malaria vaccine...
Long-term protection against malaria remains one of the greatest challenges of vaccination against this deadly parasitic disease. Whole-sporozoite (WSp) malaria vaccine formulations, which target the Plasmodium parasite's pre-erythrocytic stages, include radiation-attenuated sporozoites (RAS), early- and late-arresting genetically-attenuated parasites (EA-GAP and LA-GAP, respectively), and chemoprophylaxis with sporozoites (CPS). Although all these four vaccine formulations induce protective immune responses in the clinic, data on the longevity of the antimalarial protection they afford remain scarce. We employed a mouse model of malaria to assess protection conferred by immunization with P. berghei (Pb)-based surrogates of these four WSp formulations over a 36-week period. We show that EA-GAP WSp provide the lowest overall protection against an infectious Pb challenge, and that while immunization with RAS and LA-GAP WSp elicits the most durable protection, the protective efficacy of CPS WSp wanes rapidly over the 36-week period, most notably at higher immunization dosages. Analyses of liver immune cells show that CD44 CD8 T cells in CPS WSp-immunized mice express increased levels of the co-inhibitory PD-1 and LAG-3 markers compared to mice immunized with the other WSp formulations. This indicates that memory CD8 T cells elicited by CPS WSp immunization display a more exhausted phenotype, which may explain the rapid waning of protection conferred by the former. These results emphasize the need for a detailed comparison of the duration of protection of different WSp formulations in humans and suggest a more beneficial effect of RAS and LA-GAP WSp compared to EA-GAP or CSP WSp.
Topics: Humans; Animals; Mice; Plasmodium berghei; Sporozoites; Vaccines, Attenuated; CD8-Positive T-Lymphocytes; Lead; Malaria; Malaria Vaccines
PubMed: 38007342
DOI: 10.1016/j.vaccine.2023.11.023 -
Experimental Parasitology Dec 2014We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate...
We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate of the human parasite, Plasmodium falciparum. We analyzed the whole coding sequence of Plasmodium berghei chloroquine resistance transporter (Pbcrt) and Plasmodium berghei multidrug resistance gene 1(Pbmdr-1) for polymorphisms. These genes are associated with quinoline resistance in Plasmodium falciparum. No polymorphic changes were detected in the coding sequences of Pbcrt and Pbmdr1 or in the mRNA transcript levels of Pbmdr1. However, our data demonstrated that PQ and LM resistance is achieved by multiple mechanisms that include elevated mRNA transcript levels of V-type H(+) pumping pyrophosphatase (vp2), Ca(2+)/H(+) antiporter (vcx1), gamma glutamylcysteine synthetase (ggcs) and glutathione-S-transferase (gst) genes, mechanisms also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in ggcs and gst transcript levels was accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr1 are not associated with PQ and LM resistance in P. berghei ANKA, while vp2, vcx1, ggcs and gst may mediate resistance directly or modulate functional mutations in other unknown genes.
Topics: Animals; Antimalarials; Antiporters; Cation Transport Proteins; Cloning, Molecular; DNA, Protozoan; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Gene Expression Regulation, Enzymologic; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Lumefantrine; Male; Mice; Parasitic Sensitivity Tests; Plasmodium berghei; Quinolines; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA
PubMed: 25448357
DOI: 10.1016/j.exppara.2014.10.008 -
Malaria Journal Jun 2017Aspartate, which is converted from oxaloacetate (OAA) by aspartate aminotransferase, is considered an important precursor for purine salvage and pyrimidine de novo...
BACKGROUND
Aspartate, which is converted from oxaloacetate (OAA) by aspartate aminotransferase, is considered an important precursor for purine salvage and pyrimidine de novo biosynthesis, and is thus indispensable for the growth of Plasmodium parasites at the asexual blood stages. OAA can be produced in malaria parasites via two routes: (i) from phosphoenolpyruvate (PEP) by phosphoenolpyruvate carboxylase (PEPC) in the cytosol, or (ii) from fumarate by consecutive reactions catalyzed by fumarate hydratase (FH) and malate:quinone oxidoreductase (MQO) in the mitochondria of malaria parasites. Although PEPC-deficient Plasmodium falciparum and Plasmodium berghei (rodent malaria) parasites show a growth defect, the mutant P. berghei can still cause experimental cerebral malaria (ECM) with similar dynamics to wild-type parasites. In contrast, the importance of FH and MQO for parasite viability, growth and virulence is not fully understood because no FH- and MQO-deficient P. falciparum has been established. In this study, the role of FH and MQO in the pathogenicity of asexual-blood-stage Plasmodium parasites causing cerebral malaria was examined.
RESULTS
First, FH- and MQO-deficient parasites were generated by inserting a luciferase-expressing cassette into the fh and mqo loci in the genome of P. berghei ANKA strain. Second, the viability of FH-deficient and MQO-deficient parasites that express luciferase was determined by measuring luciferase activity, and the effect of FH or MQO deficiency on the development of ECM was examined. While the viability of FH-deficient P. berghei was comparable to that of control parasites, MQO-deficient parasites exhibited considerably reduced viability. FH activity derived from erythrocytes was also detected. This result and the absence of phenotype in FH-deficient P. berghei parasites suggest that fumarate can be metabolized to malate by host or parasite FH in P. berghei-infected erythrocytes. Furthermore, although the growth of FH- and MQO-deficient parasites was impaired, the development of ECM was suppressed only in mice infected with MQO-deficient parasites.
CONCLUSIONS
These findings suggest that MQO-mediated mitochondrial functions are required for development of ECM of asexual-blood-stage Plasmodium parasites.
Topics: Animals; Blood-Brain Barrier; Erythrocytes; Female; Fumarate Hydratase; Fumarates; Malaria, Cerebral; Malates; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Oxaloacetic Acid; Oxidoreductases; Plasmodium berghei; Specific Pathogen-Free Organisms
PubMed: 28606087
DOI: 10.1186/s12936-017-1898-5 -
Molecular and Biochemical Parasitology Jul 2021Malaria parasites exhibit a complex lifecycle, requiring extensive asexual replication in the liver and blood of the vertebrate host, and in the haemocoel of the insect... (Review)
Review
Malaria parasites exhibit a complex lifecycle, requiring extensive asexual replication in the liver and blood of the vertebrate host, and in the haemocoel of the insect vector. Yet, they must also undergo a single round of sexual reproduction, which occurs in the vector's midgut upon uptake of a blood meal. Sexual reproduction is obligate for infection of the vector and thus, is essential for onwards transmission to new hosts. Sex in malaria parasites involves several bottlenecks in parasite number, making the stages involved attractive targets for blocking disease transmission. Malaria parasites have evolved a suite of adaptations ("strategies") to maximise the success of sexual reproduction and transmission, which could undermine transmission-blocking interventions. Yet, understanding parasite strategies may also reveal novel opportunities for such interventions. Here, we outline how evolutionary and ecological theories, developed to explain reproductive strategies in multicellular taxa, can be applied to explain two reproductive strategies (conversion rate and sex ratio) expressed by malaria parasites within the vertebrate host.
Topics: Animals; Biological Coevolution; Culicidae; Erythrocytes; Female; Gametogenesis; Host-Parasite Interactions; Humans; Insect Vectors; Life Cycle Stages; Liver; Malaria; Male; Plasmodium berghei; Plasmodium chabaudi; Plasmodium falciparum; Plasmodium knowlesi; Reproduction, Asexual; Sex Ratio
PubMed: 34023299
DOI: 10.1016/j.molbiopara.2021.111375 -
Parasites & Vectors Feb 2020Mosquitoes and other vectors are often exposed to sublethal doses of insecticides. Larvae can be exposed to the run-off of agricultural use, and adults can be irritated...
BACKGROUND
Mosquitoes and other vectors are often exposed to sublethal doses of insecticides. Larvae can be exposed to the run-off of agricultural use, and adults can be irritated by insecticides used against them and move away before they have picked up a lethal dose. This sublethal exposure may affect the success of control of insect-borne diseases, for it may affect the competence of insects to transmit parasites, in particular if the insects are undernourished.
METHODS
We assessed how exposure of larvae and adults to a sublethal dose of permethrin (a pyrethroid) and how larval competition for food affect several aspects of the vector competence of the mosquito Anopheles gambiae for the malaria parasite Plasmodium berghei. We infected mosquitoes with P. berghei and measured the longevity and the prevalence and intensity of infection to test for an effect of our treatments.
RESULTS
Our general result was that the exposure to the insecticide helped mosquitoes deal with infection by malaria. Exposure of either larvae or adults decreased the likelihood that mosquitoes were infected by about 20%, but did not effect the parasite load. Exposure also increased the lifespan of infected mosquitoes, but only if they had been reared in competition. Larval competition had no effect on the prevalence of infection, but increased parasite load. These effects may be a consequence of the machinery governing oxidative stress, which underlies the responses of mosquitoes to insecticides, to food stress and to parasites.
CONCLUSIONS
We conclude that insecticide residues are likely to affect the ability of mosquitoes to carry and transmit pathogens such as malaria, irrespective of the stage at which they are exposed to the insecticide. Our results stress the need for further studies to consider sublethal doses in the context of vector ecology and vector-borne disease epidemiology.
Topics: Animals; Anopheles; Female; Insecticides; Larva; Malaria; Male; Mice; Mosquito Vectors; Oocysts; Parasite Load; Permethrin; Plasmodium berghei; Rodentia; Sporozoites
PubMed: 32106886
DOI: 10.1186/s13071-020-3983-9 -
Malaria Journal Jul 2020Malaria is one of the most prevalent infectious disease in the world with 3.2 billion humans at risk. Malaria causes splenomegaly and damage in other organs including...
BACKGROUND
Malaria is one of the most prevalent infectious disease in the world with 3.2 billion humans at risk. Malaria causes splenomegaly and damage in other organs including skeletal muscles. Skeletal muscles comprise nearly 50% of the human body and are largely responsible for the regulation and modulation of overall metabolism. It is essential to understand how malaria damages muscles in order to develop effective preventive measures and/or treatments. Using a pre-clinical animal model, the potential molecular mechanisms of Plasmodium infection affecting skeletal muscles of mice were investigated.
METHODS
Mouse Signal Transduction Pathway Finder PCR Array was used to monitor gene expression changes of 10 essential signalling pathways in skeletal muscles from mice infected with Plasmodium berghei and Plasmodium chabaudi. Then, a new targeted-lipidomic approach using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to profile 158 lipid signalling mediators (LMs), mostly eicosanoids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was applied. Finally, 16 key LMs directly associated with inflammation, oxidative stress, and tissue healing in skeletal muscles, were quantified.
RESULTS
The results showed that the expression of key genes altered by Plasmodium infection is associated with inflammation, oxidative stress, and atrophy. In support to gene profiling results, lipidomics revealed higher concentrations of LMs in skeletal muscles directly related to inflammatory responses, while on the levels of LMs crucial in resolving inflammation and tissue repair reduced significantly.
CONCLUSION
The results provide new insights into the molecular mechanisms of malaria-induced muscle damage and revealed a potential mechanism modulating inflammation in malarial muscles. These pre-clinical studies should help with future clinical studies in humans aimed at monitoring of disease progression and development of specific interventions for the prevention and mitigation of long-term chronic effects on skeletal muscle function.
Topics: Animals; Malaria; Male; Mice; Muscle, Skeletal; Plasmodium berghei; Plasmodium chabaudi
PubMed: 32664933
DOI: 10.1186/s12936-020-03332-3