Strains Of Malaria Research Articles

The dynamics of multiple species and strains of malaria

This paper presents a deterministic SIS model for the transmission dynamics of malaria, a life-threatening disease transmitted by mosquitos. Four species of the parasite genus Plasmodium are known to cause human malaria. Some species of the parasite have evolved into strains that are resistant to treatment. Although proportions of Plasmodium species vary considerably between geographic regions, multiple species and strains do coexist within some communities. The mathematical model derived here includes all available species and strains for a given community. The model has a disease-free equilibrium, which is a global attractor when the reproduction number of each species or strain is less than one. The model possesses quasi-endemic equilibria; local asymptotic stability is established for two species, and numerical simulations suggest that the species or strain with the highest reproduction number exhibits competitive exclusion.

The Dynamics of Multiple Species and Strains of Malaria

The Dynamics of Multiple Species and Strains of Malaria

Identification of Compounds with Efficacy against Malaria Parasites from Common North American Plants.

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for the treatment of malaria, drug resistance has become a widespread problem. Therefore, a critical need exists to identify new compounds that have efficacy against drug-resistant malaria strains. In the current study, extracts prepared from plants readily obtained from local sources were screened for activity against Plasmodium falciparum. Bioassay-guided fractionation was used to identify 18 compounds from five plant species. These compounds included eight lupane triterpenes (1-8), four kaempferol 3-O-rhamnosides (10-13), four kaempferol 3-O-glucosides (14-17), and the known compounds amentoflavone and knipholone. These compounds were tested for their efficacy against multi-drug-resistant malaria parasites and counterscreened against HeLa cells to measure their antimalarial selectivity. Most notably, one of the new lupane triterpenes (3) isolated from the supercritical extract of Buxus sempervirens, the common boxwood, showed activity against both drug-sensitive and -resistant malaria strains at a concentration that was 75-fold more selective for the drug-resistant malaria parasites as compared to HeLa cells. This study demonstrates that new antimalarial compounds with efficacy against drug-resistant strains can be identified from native and introduced plant species in the United States, which traditionally have received scant investigation compared to more heavily explored tropical and semitropical botanical resources from around the world.

IL-25, IL-33 and TSLP receptor are not critical for development of experimental murine malaria

IL-25, IL-33 and TSLP, which are produced predominantly by epithelial cells, can induce production of Th2-type cytokines such as IL-4, IL-5 and/or IL-13 by various types of cells, suggesting their involvement in induction of Th2-type cytokine-associated immune responses. It is known that Th2-type cytokines contribute to host defense against malaria parasite infection in mice. However, the roles of IL-25, IL-33 and TSLP in malaria parasite infection remain unclear. Thus, to elucidate this, we infected wild-type, IL-25−/−, IL-33−/− and TSLP receptor (TSLPR)−/− mice with Plasmodium berghei (P. berghei) ANKA, a murine malaria strain. The expression levels of IL-25, IL-33 and TSLP mRNA were changed in the brain, liver, lung and spleen of wild-type mice after infection, suggesting that these cytokines are involved in host defense against P. berghei ANKA. However, the incidence of parasitemia and survival in the mutant mice were comparable to in the wild-type mice. These findings indicate that IL-25, IL-33 and TSLP are not critical for host defense against P. berghei ANKA.

Maternal effects, malaria infections and the badge size of the house sparrow

The evolution of sexual signals is not only determined by immediate sexual selection but also by selection arising from the environment and the interaction with developmental effects. In this study we aimed to investigate how the badge size of male house sparrows (Passer domesticus) is correlated to avian malaria infections as well as to prenatal testosterone exposure, measured as the 2D:4D digit ratio. The rationale behind this study is that the immunosuppressive effect of maternal testosterone deposition combined with the fitness cost imposed by parasites may cause important trade-offs to the development of secondary sexual signals. Assuming that vector abundance is a key variable associated with infection risk by avian malaria, we caught adult male sparrows from eight different populations in the Camargue, France, four of which were located in a vector-controlled area, and the other four in an untreated area. For each bird we measured its badge size, digit ratio and took blood to determine its infections status. We used PCR to identify the malaria parasite species and strain that caused the infection. Contrary to our expectation, prevalence of disease did not differ across the vector-treatment regions, with around 80 % of birds being infected in both areas, and those infections were caused largely by a single strain, Plasmodium relictum SGS1. Although infected birds had a badge size not significantly different from uninfected males, there was a condition-dependent association between badge size, infection status and maternal testosterone deposition. This study illustrates that the complexity of temporal and ecological dimensions makes the relationships between disease, testosterone-related traits and secondary sexual signals that have been previously reported less general than thought.

Protective Efficacy of Malaria Vaccine Varies with Parasite Strain

The RTS,S/AS01 vaccine is based on genetic sequences derived from a single malaria strain, 3D7, but malaria parasites are genetically diverse. Now, in a partially industry-supported study, investigators have assessed differences in vaccine efficacy according to whether the parasites match the vaccine strain at the circumsporozoite protein C-terminal. The researchers used samples from RTS,S/AS01-vaccinated participants in a phase III trial conducted at 11 sites across 7 African …

ChemInform Abstract: Synthetic Chemistry Fuels Interdisciplinary Approaches to the Production of Artemisinin

AbstractReview: 59 refs.

Antimalarial Activity of Various Bisbenzylisoquinoline and AporphineBenzylisoquinoline Alkaloids and their Structure-Activity Relationships against Chloroquine – Sensitive and Resistant Plasmodium falciparum Malaria in vitro

The antimalarial activity of some bisbenzylisoquinoline (BBIQ) alkaloids were studied using in vitro culture of both chloroquine (CQ)-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The combination of chloroquine and tetrandrine gave a 44 fold potentiation of malarial killing. Fangchinoline, hernandezine, pycnamine, berbamine and isotetrandrine had similar antimalarial activity as tetrandrine against the sensitive strain of P. falciparum malaria. Hernandezine, isotetrandrine, berbamine, fangchinoline and methoxyadiantifoline had similar antimalarial activity as tetrandrine against a strain of chloroquine-resistant falciparum malaria. Based on structure/ activity analysis, we concluded that the stereochemistry of C-1E¹ (S ring) of the BBIQ structure played an important role in selective action against resistant malaria. The stereochemistry of C-1 (left ring) and a substituent of C-12 appeared to have little influence on the selectivity. The point of attachment of the ether bridges to the rings also exerts an important influence on selective antimalarial activity. Tetrandrine (TT) penetrates both the erythrocyte and parasite membranes and inhibits the synthesis and activity of the (MDR) pump and likely the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) since it inhibits the calcium channel. These observations likely account for the fact TT potentiates the activity of chloroquine more than 40 fold against chloroquine resistant falciparum malaria.

Vaccines against malaria.

Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease.

Dynamics of an age-structured two-strain model for malaria transmission

A new age-structured deterministic model for assessing the impact of anti-malaria drugs on the transmission dynamics of malaria is designed and qualitatively analysed. The resulting two-strain age-structured model undergoes backward bifurcation, which arises due to malaria-induced mortality in humans. Conditions for the existence of unique resistant strain-only and low-endemicity equilibria are derived for special cases. It is shown, for the case when treatment does not cause drug resistance, that the disease-free equilibrium of the wild strain-only component of the model is globally-asymptotically stable whenever the associated reproduction number of the model is less than unity. Similar result is established for the resistant strain-only component of the model for this case. Numerical simulations of the model, for the case when treatment does not cause drug resistance, show that the model undergoes competitive exclusion (where the malaria strain with the higher reproduction number drives the other to extinction).

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand’s Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2–12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50=86nM (3D7 strain), 201nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure–activity relationships have been identified for the antimalarial activity in these abietane analogues.

Prevalence and beta diversity in avian malaria communities: host species is a better predictor than geography.

Patterns of diversity and turnover in macroorganism communities can often be predicted from differences in habitat, phylogenetic relationships among species and the geographical scale of comparisons. In this study, we asked whether these factors also predict diversity and turnover in parasite communities. We studied communities of avian malaria in two sympatric, ecologically similar, congeneric host species at three different sites. We asked whether parasite prevalence and community structure varied with host population, host phylogeography or geographical distance. We used PCR to screen birds for infections and then used Bayesian methods to determine phylogenetic relationships among malaria strains. Metrics of both community and phylogenetic beta diversity were used to examine patterns of malaria strain turnover between host populations, and partial Mantel tests were used determine the correlation between malaria beta diversity and geographical distance. Finally, we developed microsatellite markers to describe the genetic structure of host populations and assess the relationship between host phylogeography and parasite beta diversity. We found that different genera of malaria parasites infect the two hosts at different rates. Within hosts, parasite communities in one population were phylogenetically clustered, but there was otherwise no correlation between metrics of parasite beta diversity and geographical or genetic distance between host populations. Patterns of parasite turnover among host populations are consistent with malaria transmission occurring in the winter rather than on the breeding grounds. Our results indicate greater turnover in parasite communities between different hosts than between different study sites. Differences in host species, as well as transmission location and vector ecology, seem to be more important in structuring malaria communities than the distance-decay relationships frequently found in macroorganisms. Determining the factors affecting parasite community diversity and turnover has wide-ranging implications for understanding the selective pressures shaping host ecology and ecosystem structure. This study shows that metrics of community and phylogenetic beta diversity can be useful tools for disentangling the ecological and evolutionary processes that underlie geographical variation in parasite communities.

A Mathematical Model for the Transmission and Spread of Drug Sensitive and Resistant Malaria Strains within a Human Population

Malaria remains by far the world's most important tropical disease, killing more people than any other communicable disease. A number of preventive and control measures have been put in place and most importantly drug treatment. The emergence of drug resistance against the most common and affordable antimalarials is widespread and poses a key obstacle to malaria control. A mathematical model that incorporates evolution of drug resistance and treatment as a preventive strategy is formulated and analyzed. The qualitative analysis of the model is given in terms of the effective reproduction number, Re. The existence and stability of the disease-free and endemic equilibria of the model are studied. We establish the threshold parameters below which the burden due to malaria can be brought under control. Numerical simulations are done to determine the role played by key parameters in the model. The public health implications of the results are twofold; firstly every effort should be taken to minimize the evolution of drug resistance due to treatment failure and secondly high levels of treatment and development of immunity are essential in reducing the malaria burden.

Probing the ubiquinol-binding site of recombinant Sauromatum guttatum alternative oxidase expressed in E. coli membranes through site-directed mutagenesis

In the present paper we have investigated the effect of mutagenesis of a number of highly conserved residues (R159, D163, L177 and L267) which we have recently shown to line the hydrophobic inhibitor/substrate cavity in the alternative oxidases (AOXs). Measurements of respiratory activity in rSgAOX expressed in Escherichia coli FN102 membranes indicate that all mutants result in a decrease in maximum activity of AOX and in some cases (D163 and L177) a decrease in the apparent Km (O2). Of particular importance was the finding that when the L177 and L267 residues, which appear to cause a bottleneck in the hydrophobic cavity, are mutated to alanine the sensitivity to AOX antagonists is reduced. When non-AOX anti-malarial inhibitors were also tested against these mutants widening the bottleneck through removal of isobutyl side chain allowed access of these bulkier inhibitors to the active-site and resulted in inhibition. Results are discussed in terms of how these mutations have altered the way in which the AOX's catalytic cycle is controlled and since maximum activity is decreased we predict that such mutations result in an increase in the steady state level of at least one O2-derived AOX intermediate. Such mutations should therefore prove to be useful in future stopped-flow and electron paramagnetic resonance experiments in attempts to understand the catalytic cycle of the alternative oxidase which may prove to be important in future rational drug design to treat diseases such as trypanosomiasis. Furthermore since single amino acid mutations in inhibitor/substrate pockets have been found to be the cause of multi-drug resistant strains of malaria, the decrease in sensitivity to main AOX antagonists observed in the L-mutants studied in this report suggests that an emergence of drug resistance to trypanosomiasis may also be possible. Therefore we suggest that the design of future AOX inhibitors should have structures that are less reliant on the orientation by the two-leucine residues. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

Whether Plasmodium Knowlesi will be a Future threat for India?

Fifth strain of human malaria is plasmodium knowlesi which is mimicking like plasmodium Falciparum and Plasmodium Malariae. It is fatal disease in human which is common in Southeast Asia. The incubation period for P. knowlesi is about 12 days - the shortest known malaria of all the known malarias that infect humans and primates. P knowlesi has a 24 hour asexual cycle and the clinical features are Headache, fever -quotidian, chills and cold sweats, respiratory distress and it extent to renal failure, liver failure. The disease can be treated using already existing anti-malaria therapy such as mefloquine and chloroquine. Chloroquine is specifically preferred for non-complicated infections. Prevention -Stop deforestation and avoid Jungle travelling. The vector for plasmodium knowlesi is anopheles group of mosquito and the reservoir is long tailed monkeys. In Indian context the vector is present in south and northeast part of India and the reservoir is present in Nicobar Islands. There is possibility of fifth strain of human malariae in India.

Investigations of Artemisia Annua and Artemisia Sieberi Water Extracts Inhibitory Effects on Β-Hematin Formation

Malaria is the most prevalent infectious disease in the world, killing 1-2 million people each year. New drugs are urgently needed to treat drug-resistant strains of malaria. In a previous study we found that extracts from Salvia palestinia leaves inhibited the formation of β-hematin with efficiency similar to that of chloroquine. The objective of this study was to investigate the effect of other plant extracts on hemozoin formation. A comparison between the efficiency of aqueous extracts or infusions of Artemisia annua from Luxembourg and Artemisia sieberi from Palestine in inhibiting β-hematin formation was done. Although it was found that the Artemisia sieberi leaf tea infusion was less effective than that of the Artemisia annua, the stem infusion of Artemisia sieberi was found to be better than that of Artemisia annua stems. Results obtained with infusions prepared with tap or well water may be different from results obtained in the laboratory with distilled water. Artemisia annua leaf infusions prepared using salt water (0.5g salt/150ml water) had higher efficiency in inhibiting β-hematin formation than those infusions done with distilled water. Mixing equal amounts of Artemisia annua leaf and Artemisia sieberi stem water extract showed an increase in their inhibitory effect on β-hematin formation. An important finding in this investigation was that the Artemisia annua lyophilized extracts lost activity with time, which may have an impact not only on in vitro laboratory results but also on in vivo treatment efficiency obtained with old extracts. In light of this finding it might be advisable to use Artemisia annua in the form of dried leaf powder and not in the form of extracts or infusion. Stored in dry, ventilated conditions the plant keeps its properties for many years.

The ubiquitin system: an essential component to unlocking the secrets of malaria parasite biology.

Exploration of the ubiquitin system in eukaryotes has shown that the chemical modification of proteins by ubiquitin, known as ubiquitylation, is an incredibly important post-translational event that is crucial to numerous cellular processes. Ubiquitylation is carried out by a series of enzymes that specifically target proteins to either change their activity or their location or earmark them for degradation. Using a wide range of genome-wide approaches, the ubiquitin system has been shown to be of particular importance in the survival and propagation of the human malaria parasites. In this review, we highlight our current understanding of the ubiquitin system in Plasmodium, and discuss its possible role in the development of drug resistant malaria strains.

PUMA: A Puzzle Piece in Chloroquine’s Antimelanoma Activity

Chloroquine can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. While it is well known that chloroquine impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of chloroquine and the subsequent cascade of events that leads to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, chloroquine induces apoptosis by preventing degradation of the pro-apoptotic BH3-only protein PUMA. This finding adds to the unfolding story of chloroquine’s mechanism of action as a cancer therapeutic agent.

Proposal for a new therapy for drug-resistant malaria using Plasmodium synthetic lethality inference

Many antimalarial drugs kill malaria parasites, but antimalarial drug resistance (ADR) and toxicity to normal cells limit their usefulness. To solve this problem, we suggest a new therapy for drug-resistant malaria. The approach consists of data integration and inference through homology analysis of yeast–human–Plasmodium. If one gene of a Plasmodium synthetic lethal (SL) gene pair has a mutation that causes ADR, a drug targeting the other gene of the SL pair might be used as an effective treatment for drug-resistant strains of malaria. A simple computational tool to analyze the inferred SL genes of Plasmodium species (malaria parasites Plasmodium falciparum and Plasmodium vivax for human malarial therapy, and rodent parasite Plasmodium berghei for in vivo studies of human malarias) was established to identify SL genes that can be used as drug targets. Information on SL gene pairs with ADR genes and their first neighbors was inferred from yeast SL genes to search for pertinent antimalarial drug targets. We not only suggest drug target gene candidates for further experimental validation, but also provide information on new usage for already-described drugs. The proposed specific antimalarial drug candidates can be inferred by searching drugs that cause a fitness defect in yeast SL genes.