Variation In Malaria Research Articles

Global malaria predictors at a localized scale

Malaria is a life-threatening disease caused by Plasmodium parasites transmitted by Anopheles mosquitoes. In 2022, more than 249 million cases of malaria were reported worldwide, with an estimated 608,000 deaths. While malaria incidence has decreased globally in recent decades, some public health gains have plateaued, and many endemic hotspots still face high transmission rates. Understanding local drivers of malaria transmission is crucial but challenging due to the complex interactions between climate, entomological and human variables, and land use. This study focuses on highly climatically suitable and endemic areas in Côte d’Ivoire to assess the explanatory power of coarse climatic predictors of malaria transmission at a fine scale. Using data from 40 villages participating in a randomized controlled trial of a household malaria intervention, the study examines the effects of climate variation over time on malaria transmission. Through panel regressions and statistical modeling, the study investigates which variable (temperature, precipitation, or entomological inoculation rate) and its form (linear or unimodal) best explains seasonal malaria transmission and the factors predicting spatial variation in transmission. The results highlight the importance of temperature and rainfall, with quadratic temperature and all precipitation models performing well, but the causal influence of each driver remains unclear due to their strong correlation. Further, an independent, mechanistic temperature-dependent R0 model based on laboratory data, which predicts that malaria transmission peaks at 25°C and declines at lower and higher temperatures, aligns well with observed malaria incidence rates, emphasizing the significance and predictability of temperature suitability across scales. By contrast, entomological variables, such as entomological inoculation rate, were not strong predictors of human incidence in this context. Finally, the study explores the predictors of spatial variation in malaria, considering land use, intervention, and entomological variables. The findings contribute to a better understanding of malaria transmission dynamics at local scales, aiding in the development of effective control strategies in endemic regions.

Modelling and mapping the intra-urban spatial distribution of Plasmodium falciparum parasite rate using very-high-resolution satellite derived indicators

BackgroundThe rapid and often uncontrolled rural–urban migration in Sub-Saharan Africa is transforming urban landscapes expected to provide shelter for more than 50% of Africa’s population by 2030. Consequently, the burden of malaria is increasingly affecting the urban population, while socio-economic inequalities within the urban settings are intensified. Few studies, relying mostly on moderate to high resolution datasets and standard predictive variables such as building and vegetation density, have tackled the topic of modeling intra-urban malaria at the city extent. In this research, we investigate the contribution of very-high-resolution satellite-derived land-use, land-cover and population information for modeling the spatial distribution of urban malaria prevalence across large spatial extents. As case studies, we apply our methods to two Sub-Saharan African cities, Kampala and Dar es Salaam.MethodsOpenly accessible land-cover, land-use, population and OpenStreetMap data were employed to spatially model Plasmodium falciparum parasite rate standardized to the age group 2–10 years (PfPR2–10) in the two cities through the use of a Random Forest (RF) regressor. The RF models integrated physical and socio-economic information to predict PfPR2–10 across the urban landscape. Intra-urban population distribution maps were used to adjust the estimates according to the underlying population.ResultsThe results suggest that the spatial distribution of PfPR2–10 in both cities is diverse and highly variable across the urban fabric. Dense informal settlements exhibit a positive relationship with PfPR2–10 and hotspots of malaria prevalence were found near suitable vector breeding sites such as wetlands, marshes and riparian vegetation. In both cities, there is a clear separation of higher risk in informal settlements and lower risk in the more affluent neighborhoods. Additionally, areas associated with urban agriculture exhibit higher malaria prevalence values.ConclusionsThe outcome of this research highlights that populations living in informal settlements show higher malaria prevalence compared to those in planned residential neighborhoods. This is due to (i) increased human exposure to vectors, (ii) increased vector density and (iii) a reduced capacity to cope with malaria burden. Since informal settlements are rapidly expanding every year and often house large parts of the urban population, this emphasizes the need for systematic and consistent malaria surveys in such areas. Finally, this study demonstrates the importance of remote sensing as an epidemiological tool for mapping urban malaria variations at large spatial extents, and for promoting evidence-based policy making and control efforts.

Malaria and the climate in Karachi: An eight year review.

Background and Objective:Malaria is an arthropod-borne infectious disease transmitted by the mosquito Anopheles and claims millions of lives globally every year. Reasons for failure to eradicate this disease are multifactorial. The seasonality of the malaria is principally determined by climatic factors conducive for breeding of the vector. We aimed to study the relationship between climatic variability and the seasonality of malaria over an eight-year duration.Methods:This was a retrospective medical chart review of 8,844 confirmed cases of malaria which presented to The Indus Hospital, Karachi from January 2008 to November 2015. Cases were plotted against meteorological data for Karachi to elicit monthly variation.Results:A secular incline and seasonality in malaria cases over the duration of eight years was seen. More cases were reported in the summer, rainy season compared with the other three seasons in each year. There was significant association with specific climate variables such as temperature, moisture, and humidity.Conclusion:There is a marked seasonal variation of malaria in Karachi, influenced by various environmental factors. Identification of the ‘the concentrated period’ of malaria can be helpful for policymakers to deploy malaria control interventions.

Plasmodium knowlesi: a superb in vivo nonhuman primate model of antigenic variation in malaria.

Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi - macaque model systems and summarizing exciting new progress in this area of research.

The Pattern of Variation between Diarrhea and Malaria Coexistence with Corresponding Risk Factors in, Chikhwawa, Malawi: A Bivariate Multilevel Analysis.

Developing countries face a huge burden of infectious diseases, a number of which co-exist. This paper estimates the pattern and variation of malaria and diarrhea coexistence in Chikhwawa, a district in Southern Malawi using bivariate multilevel modelling with Bayesian estimation. A probit link was employed to examine hierarchically built data from a survey of individuals (n = 6,727) nested within households (n = 1,380) nested within communities (n = 33). Results show significant malaria [ ] and diarrhea [ ] variations with a strong correlation between them [] at household level. There are significant malaria [] and diarrhea [] variations at community level but with a small correlation [] between them. There is also significant correlation between malaria and diarrhea at individual level [0.241]. These results suggest a close association between reported malaria-like illness and diarrheal illness especially at household and individual levels in Southern Malawi.

Malaria control in Botswana, 2008–2012: the path towards elimination

BackgroundBotswana has made substantial progress towards malaria elimination across the country. This work assessed interventions and epidemiological characteristics of malaria in Botswana, during a period of decreasing transmission intensity.MethodsNational passive malaria surveillance data for five years (2008–2012) were analysed. A district-level, random effects model with Poisson regression was used to explore the association between malaria cases and coverage with long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS). Malaria cases were mapped to visualize spatio-temporal variation in malaria for each year.ResultsWithin five years, a reduction in malaria prevalence (approximately 98%) and number of deaths (12 to three) was observed. Between 2008 and 2012, 237,050 LLINs were distributed and 596,979 rooms were sprayed with insecticides. Coverage with LLINs and IRS was not uniformly distributed over the study period and only targeted the northern districts with a high malaria burden. The coverage of IRS was associated with a reduction in malaria cases.ConclusionsBotswana has made significant strides towards its goal of country-wide elimination of malaria. A major challenge in the future will be prevention and management of imported malaria infections from neighbouring countries. In order to accurately monitor progress towards the elimination goal, the malaria control programme (NMP) should strengthen the reporting and capturing of data at household and individual level. Systematic, periodic operational research to feedback the NMP will help to guide and achieve elimination.

The changing burden of malaria and association with vector control interventions in Zambia using district-level surveillance data, 2006–2011

BackgroundMalaria control was strengthened in Zambia over the past decade. The two primary interventions for vector control are indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs). Using passive malaria surveillance data collected from 2006 to 2011 through the Zambian District Health Information System, the associations between increased coverage with LLINs and IRS and the burden of malaria in Zambia were evaluated.MethodsNational passive malaria surveillance data from 2006 to 2011 were analysed. A district-level, random-effects model with Poisson regression was used to explore the association between malaria cases and coverage with LLINs and IRS. Malaria cases and LLINs and IRS coverage were mapped to visualize spatiotemporal variation in malaria for each year.ResultsFrom 2006–2011, 24.6 million LLINs were distributed and 6.4 million houses were sprayed with insecticide. Coverage with LLINs was not uniformly distributed over the study period and IRS was targeted to central and southern districts where malaria transmission was low. LLIN coverage was associated with a reduction in malaria cases, although an increase in the number of malaria cases was reported in some districts over the study period. A high burden of malaria persisted in north-eastern Zambia, whereas a reduction in the number of reported malaria cases was observed in western and southern Zambia.ConclusionEnhanced and targeted interventions in north-eastern Zambia where the burden of malaria remains high, as well as efforts to sustain low malaria transmission in the south-west, will be necessary for Zambia to achieve the national goal of being malaria free by 2030.

Spatial distribution of malaria problem in three regions of Ethiopia

BackgroundThe transmission of malaria is the leading public health problem in Ethiopia. From the total area of Ethiopia, more than 75% is malarious. The aim of this study was to identify socio-economic, geographic and demographic risk factors of malaria based on the rapid diagnosis test (RDT) survey results and produce the prevalence map of the area illustrating variation in malaria risk.MethodsThis study accounts for spatial correlation in assessing the effects of socio- economic, demographic and geographic factors on the prevalence of malaria in Ethiopia. A total of 224 clusters of about 25 households each were selected from the Amhara, Oromiya and Southern Nation Nationalities and People’s (SNNP) regions of Ethiopia. A generalized linear mixed model with spatial covariance structure was used to analyse the data where the response variable was the presence or absence of malaria using the RDT.ResultsThe results showed that households in the SNNP region were found to be at more risk than Amhara and Oromiya regions. Moreover, households which have toilet facilities clean drinking water, and a greater number of rooms and mosquito nets in the rooms, have less chance of having household members testing positive for RDT. Moreover, from this study, it can be suggested that incorporating spatial variability is necessary for understanding and devising the most appropriate strategies to reduce the risk of malaria.

Nuclear Repositioning Precedes Promoter Accessibility and Is Linked to the Switching Frequency of a Plasmodium falciparum Invasion Gene

Variation of surface adhesins, such as the Plasmodium falciparum erythrocyte invasion ligand PfRh4, is critical for virulence and immune evasion in many microbes. While phenotypic switching is linked to transcriptional changes and chromatin function, the determinants of switching frequency remain poorly defined. By expressing a prokaryotic DNA methylase in P.falciparum, we directly assayed accessibility of transcriptionally active and silent chromatin at the PfRh4 locus. Parasites selected for invivo PfRh4 activation show a reversible increase in promoter accessibility and exhibit perinuclear repositioning of the locus from a silent to a conserved activation domain. Forced activation of a proximal gene results in a similar repositioning of the PfRh4 locus, witha concomitant increase in PfRh4 activation ina subpopulation of parasites and promoter accessibility correlating with actively transcribed loci. Thus, nuclear repositioning is associated with increased P.falciparum switching frequency, while promoter accessibility is tightly linked to clonally active PfRh4 promoters.

Symmetry Breaking in a Model of Antigenic Variation with Immune Delay

Effects of immune delay on symmetric dynamics are investigated within a model of antigenic variation in malaria. Using isotypic decomposition of the phase space, stability problem is reduced to the analysis of a cubic transcendental equation for the eigenvalues. This allows one to identify periodic solutions with different symmetries arising at a Hopf bifurcation. In the case of small immune delay, the boundary of the Hopf bifurcation is found in a closed form in terms of system parameters. For arbitrary values of the time delay, general expressions for the critical time delay are found, which indicate bifurcation to an odd or even periodic solution. Numerical simulations of the full system are performed to illustrate different types of dynamical behaviour. The results of this analysis are quite generic and can be used to study within-host dynamics of many infectious diseases.

The effects of symmetry on the dynamics of antigenic variation

In the studies of dynamics of pathogens and their interactions with a host immune system, an important role is played by the structure of antigenic variants associated with a pathogen. Using the example of a model of antigenic variation in malaria, we show how many of the observed dynamical regimes can be explained in terms of the symmetry of interactions between different antigenic variants. The results of this analysis are quite generic, and have wider implications for understanding the dynamics of immune escape of other parasites, as well as for the dynamics of multi-strain diseases.

Rapid whole genome optical mapping of Plasmodium falciparum

BackgroundImmune evasion and drug resistance in malaria have been linked to chromosomal recombination and gene copy number variation (CNV). These events are ideally studied using comparative genomic analyses; however in malaria these analyses are not as common or thorough as in other infectious diseases, partly due to the difficulty in sequencing and assembling complete genome drafts. Recently, whole genome optical mapping has gained wide use in support of genomic sequence assembly and comparison. Here, a rapid technique for producing whole genome optical maps of Plasmodium falciparum is described and the results of mapping four genomes are presented.MethodsFour laboratory strains of P. falciparum were analysed using the Argus™ optical mapping system to produce ordered restriction fragment maps of all 14 chromosomes in each genome. Plasmodium falciparum DNA was isolated directly from blood culture, visualized using the Argus™ system and assembled in a manner analogous to next generation sequence assembly into maps (AssemblyViewer™, OpGen Inc.®). Full coverage maps were generated for P. falciparum strains 3D7, FVO, D6 and C235. A reference P. falciparum in silico map was created by the digestion of the genomic sequence of P. falciparum with the restriction enzyme AflII, for comparisons to genomic optical maps. Maps were then compared using the MapSolver™ software.ResultsGenomic variation was observed among the mapped strains, as well as between the map of the reference strain and the map derived from the putative sequence of that same strain. Duplications, deletions, insertions, inversions and misassemblies of sizes ranging from 3,500 base pairs up to 78,000 base pairs were observed. Many genomic events occurred in areas of known repetitive sequence or high copy number genes, including var gene clusters and rifin complexes.ConclusionsThis technique for optical mapping of multiple malaria genomes allows for whole genome comparison of multiple strains and can assist in identifying genetic variation and sequence contig assembly. New protocols and technology allowed us to produce high quality contigs spanning four P. falciparum genomes in six weeks for less than $1,000.00 per genome. This relatively low cost and quick turnaround makes the technique valuable compared to other genomic sequencing technologies for studying genetic variation in malaria.

Insecticide treated nets, antimalarials and child survival in India

Malaria has been a complex public health problem affecting mainly the poor and the rural communities in India. Insecticide treated nets (ITN) and antimalarials are the two proven interventions for prevention and control of malaria. ITN has been amply demonstrated to be an effective intervention to protect children from malaria, and in preventing deaths due to falciparum malaria. Antimalarials are a therapeutic intervention for management of malaria, and prevention of complications due to Plasmodium falciparum infection. However, implementation of these interventions is fraught with problems of complex and multidimensional nature at the periphery. These can be addressed by optimizing the use of the 2 interventions, the insecticide treated nets and antimalarials, for area specific application and country specific needs, determined by the eco-epidemiological diversity of malaria in India. This article reviews the significant role of ITN in reducing child mortality, and the judicious use of antimalarials in the management of malaria patient, and the problems associated with the use of these interventions in protecting children against malaria in India.

Parasite-host interaction in malaria: genetic clues and copy number variation

In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction.

Stability and bifurcations in a model of antigenic variation in malaria

We examine the properties of a recently proposed model for antigenic variation in malaria which incorporates multiple epitopes and both long-lasting and transient immune responses. We show that in the case of a vanishing decay rate for the long-lasting immune response, the system exhibits the so-called "bifurcations without parameters" due to the existence of a hypersurface of equilibria in the phase space. When the decay rate of the long-lasting immune response is different from zero, the hypersurface of equilibria degenerates, and a multitude of other steady states are born, many of which are related by a permutation symmetry of the system. The robustness of the fully symmetric state of the system was investigated by means of numerical computation of transverse Lyapunov exponents. The results of this exercise indicate that for a vanishing decay of long-lasting immune response, the fully symmetric state is not robust in the substantial part of the parameter space, and instead all variants develop their own temporal dynamics contributing to the overall time evolution. At the same time, if the decay rate of the long-lasting immune response is increased, the fully symmetric state can become robust provided the growth rate of the long-lasting immune response is rapid.

Immune response to a malaria infection: properties of a mathematical model†

We establish some properties of a within host mathematical model of malaria proposed by Recker et al. [M. Recker et al., Transient cross-reactive immune responses can orchestrate antigenic variation in malaria, Lett. Nature 429 (2004), pp. 555–558; M. Recker and S. Gupta, Conflicting immune responses can prolong the length of infection in Plasmodium falciparum malaria, Bull. Math. Biol. 68 (2006), pp. 821–835.], which includes the role of the immune system during the infection. The model accounts for the antigenic variation exhibited by the malaria parasite (Plasmodium falciparum). We show that the model can exhibit a wide variety of dynamical behaviours. We provide criteria for global stability, competitive exclusion and persistence. We also demonstrate that the disease equilibrium can be destabilized by non-symmetric cross-reactive responses.

Structural Basis for the EBA-175 Erythrocyte Invasion Pathway of the Malaria Parasite Plasmodium falciparum

Erythrocyte binding antigen 175 (EBA-175) is a P. falciparum protein that binds the major glycoprotein found on human erythrocytes, glycophorin A, during invasion. Here we present the crystal structure of the erythrocyte binding domain of EBA-175, RII, which has been established as a vaccine candidate. Binding sites for the heavily sialylated receptor glycophorin A are proposed based on a complex of RII with a glycan that contains the essential components required for binding. The dimeric organization of RII displays two prominent channels that contain four of the six observed glycan binding sites. Each monomer consists of two Duffy binding-like (DBL) domains (F1 and F2). F2 more prominently lines the channels and makes the majority of the glycan contacts, underscoring its role in cytoadherence and in antigenic variation in malaria. Our studies provide insight into the mechanism of erythrocyte invasion by the malaria parasite and aid in rational drug design and vaccines.

A mathematical model for a new mechanism of phenotypic variation in malaria

The Py235 merozoite rhoptry protein of the rodent malaria agent Plasmodium (yoelii) yoeli is encoded by the Py235 multigene family whose members are transcribed during the parasite's asexual life-cycle in a fashion where single schizonts subsequently give rise to sets of merozoites containing distinct Py235 transcripts. Homologues of Py235 are found in other malaria species, and antibodies to both Py235 and P. falciparum homologues inhibit merozoite invasion, suggesting a unique survival strategy involving immune evasion and host adaptation. Using a mathematical approach to model this free-living stage of Plasmodium in interaction with specific antibodies and a heterogeneous red blood cell population, we investigate if, and under what conditions, this mechanism of clonal phenotypic variation can play a role in immune evasion and adaptation to a dynamic erythropoietic environment.

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.

Antigenic variation at the infected red cell surface in malaria.

Many pathogens that either rely on an insect vector to complete their life cycle (e.g., Trypanosoma spp. and Borrelia spp.) or exist in a unique ecological niche where transmission from host to host is sporadic (e.g., Neisseria spp.) have evolved strategies to maintain infection of their mammalian hosts for long periods of time in order to ensure their survival. Because they have to survive in the face of a fully functional immune system, a common feature of many of these organisms is their development of sophisticated strategies for immune evasion. For the above organisms and for malaria parasites of the genus Plasmodium, a common theme is the ability to undergo clonal antigenic variation. In all cases, surface molecules that are important targets of the humoral immune response are encoded in the genome as multicopy, nonallelic gene families. Antigenic variation is accomplished by the successive expression of members of these gene families that show little or no immunological cross-reactivity. In the case of malaria parasites, however, some of the molecules that undergo antigenic variation are also major virulence factors, adding an additional level of complication to the host-parasite interaction. In this review, we cover the history of antigenic variation in malaria and then summarize the more recent data with particular emphasis on Plasmodium falciparum, the etiological agent of the most severe form of human malaria.