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Heliyon Mar 2024Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with...
Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential lactate dehydrogenase (LDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC values of 1.6, 2.5 and 3.1 μM, respectively. Meanwhile, MS87 (EC of 1.85 μM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective inhibitors (EC of 3.6 and 5.1 μM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC > 82 μM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.
PubMed: 38495201
DOI: 10.1016/j.heliyon.2024.e27462 -
Scientific Reports Mar 2024The parasite Plasmodium knowlesi has been the sole cause of malaria in Malaysia from 2018 to 2022. The persistence of this zoonotic species has hampered Malaysia's...
The parasite Plasmodium knowlesi has been the sole cause of malaria in Malaysia from 2018 to 2022. The persistence of this zoonotic species has hampered Malaysia's progress towards achieving the malaria-free status awarded by the World Health Organisation (WHO). Due to the zoonotic nature of P. knowlesi infections, it is important to study the prevalence of the parasite in the macaque host, the long-tailed macaque (Macaca fascicularis). Apart from P. knowlesi, the long-tailed macaque is also able to harbour Plasmodium cynomolgi, Plasmodium inui, Plasmodium caotneyi and Plasmodium fieldi. Here we report the prevalence of the 5 simian malaria parasites in the wild long-tailed macaque population in 12 out of the 13 states in Peninsular Malaysia using a nested PCR approach targeting the 18s ribosomal RNA (18s rRNA) gene. It was found that all five Plasmodium species were widely distributed throughout Peninsular Malaysia except for states with major cities such as Kuala Lumpur and Putrajaya. Of note, Pahang reported a malaria prevalence of 100% in the long-tailed macaque population, identifying it as a potential hotspot for zoonotic transmission. Overall, this study shows the distribution of the 5 simian malaria parasite species throughout Peninsular Malaysia, the data of which could be used to guide future malaria control interventions to target zoonotic malaria.
Topics: Animals; Macaca fascicularis; Malaysia; Prevalence; Malaria; Plasmodium knowlesi; Parasites
PubMed: 38472278
DOI: 10.1038/s41598-024-54981-2 -
Frontiers in Cellular and Infection... 2024, the most widespread human malaria parasite, and , an emerging that infects humans, are the phylogenetically closest malarial species that infect humans, which may...
, the most widespread human malaria parasite, and , an emerging that infects humans, are the phylogenetically closest malarial species that infect humans, which may induce cross-species reactivity across most co-endemic areas in Southeast Asia. The thrombospondin-related anonymous protein (TRAP) family is indispensable for motility and host cell invasion in the growth and development of parasites. The merozoite-specific TRAP (MTRAP), expressed in blood-stage merozoites, is supposed to be essential for human erythrocyte invasion. We aimed to characterize MTRAPs in blood-stage and parasites and ascertain their cross-species immunoreactivity. Recombinant and MTRAPs of full-length ectodomains were expressed in a mammalian expression system. The MTRAP-specific immunoglobulin G, obtained from immune animals, was used in an immunofluorescence assay for subcellular localization and invasion inhibitory activity in blood-stage parasites was determined. The cross-species humoral immune responses were analyzed in the sera of patients with or infections. The MTRAPs of (PvMTRAP) and (PkMTRAP) were localized on the rhoptry body of merozoites in blood-stage parasites. Both anti-PvMTRAP and anti-PkMTRAP antibodies inhibited erythrocyte invasion of blood-stage parasites. The humoral immune response to PvMTRAP showed high immunogenicity, longevity, and cross-species immunoreactivity with . MTRAPs are promising candidates for development of vaccines and therapeutics against vivax and knowlesi malaria.
Topics: Animals; Humans; Plasmodium vivax; Parasites; Merozoites; Thrombospondins; Plasmodium; Malaria; Malaria, Vivax; Protozoan Proteins; Mammals
PubMed: 38465236
DOI: 10.3389/fcimb.2024.1354880 -
Frontiers in Immunology 2024Human malaria, caused by five Plasmodium species (, and ), remains a significant global health burden. While most interventions target , the species associated with high...
Identification of conserved cross-species B-cell linear epitopes in human malaria: a subtractive proteomics and immuno-informatics approach targeting merozoite stage proteins.
Human malaria, caused by five Plasmodium species (, and ), remains a significant global health burden. While most interventions target , the species associated with high mortality rates and severe clinical symptoms, non-falciparum species exhibit different transmission dynamics, remain hugely neglected, and pose a significant challenge to malaria elimination efforts. Recent studies have reported the presence of antigens associated with cross-protective immunity, which can potentially disrupt the transmission of various Plasmodium species. With the sequencing of the Plasmodium genome and the development of immunoinformatic tools, in this study, we sought to exploit the evolutionary history of Plasmodium species to identify conserved cross-species B-cell linear epitopes in merozoite proteins. We retrieved Plasmodium proteomes associated with human malaria and applied a subtractive proteomics approach focusing on merozoite stage proteins. Bepipred 2.0 and Epidope were used to predict B-cell linear epitopes using as the reference species. The predictions were further compared against human and non-falciparum databases and their antigenicity, toxicity, and allergenicity assessed. Subsequently, epitope conservation was carried out using locally sequenced isolates from a malaria-endemic region in western Kenya (n=27) and Kenyan isolates from MalariaGEN version 6 (n=131). Finally, physiochemical characteristics and tertiary structure of the B-cell linear epitopes were determined. The analysis revealed eight epitopes that showed high similarity (70-100%) between falciparum and non-falciparum species. These epitopes were highly conserved when assessed across local isolates and those from the MalariaGEN database and showed desirable physiochemical properties. Our results show the presence of conserved cross-species B-cell linear epitopes that could aid in targeting multiple Plasmodium species. Nevertheless, validating their efficacy and experimentally is essential.
Topics: Animals; Humans; Merozoites; Epitopes, B-Lymphocyte; Kenya; Proteomics; Plasmodium falciparum; Plasmodium vivax; Malaria; Malaria, Falciparum; Plasmodium; Malaria, Vivax
PubMed: 38404581
DOI: 10.3389/fimmu.2024.1352618 -
MethodsX Jun 2024Mosquito-borne diseases pose a significant threat in many Southeast Asian countries, particularly through the sylvatic cycle, which has a wildlife reservoir in forests...
Mosquito-borne diseases pose a significant threat in many Southeast Asian countries, particularly through the sylvatic cycle, which has a wildlife reservoir in forests and rural areas. Studying the composition and diversity of vectors and pathogen transmission is especially challenging in forests and rural areas due to their remoteness, limited accessibility, lack of power, and underdeveloped infrastructure. This study is based on the WHO mosquito sampling protocol, modifies technical details to support mosquito collection in difficult-to-access and resource-limited areas. Specifically, we describe the procedure for using rechargeable lithium batteries and solar panels to power the mosquito traps, demonstrate a workflow for processing and storing the mosquitoes in a -20 °C freezer, data management tools including microclimate data, and quality assurance processes to ensure the validity and reliability of the results. A pre- and post-test was utilized to measure participant knowledge levels. Additional research is needed to validate this protocol for monitoring vector-borne diseases in hard-to-reach areas within other countries and settings.
PubMed: 38328504
DOI: 10.1016/j.mex.2024.102563 -
Malaria Journal Jan 2024A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In...
BACKGROUND
A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In many near-elimination settings in Southeast Asia, it is known that forest-goers are at higher risk for malaria infection, but detailed information on their behaviours and exposures is not available.
METHODS
In Aceh Province, Indonesia, a near-elimination setting where a growing proportion of malaria is due to Plasmodium knowlesi, a case-control study was conducted to identify risk factors for symptomatic malaria, characteristics of forest-goers, and key intervention points. From April 2017 to September 2018, cases and controls were recruited and enrolled in a 1:3 ratio. Cases had confirmed malaria infection by rapid diagnostic test or microscopy detected at a health facility (HF). Gender-matched controls were recruited from passive case detection among individuals with suspected malaria who tested negative at a health facility (HF controls), and community-matched controls were recruited among those testing negative during active case detection. Multivariable logistic regression (unconditional for HF controls and conditional for community controls) was used to identify risk factors for symptomatic malaria infection.
RESULTS
There were 45 cases, of which 27 were P. knowlesi, 17 were Plasmodium vivax, and one was not determined. For controls, 509 and 599 participants were recruited from health facilities and the community, respectively. Forest exposures were associated with high odds of malaria; in particular, working and sleeping in the forest (HF controls: adjusted odds ratio (aOR) 21.66, 95% CI 5.09-92.26; community controls: aOR 16.78, 95% CI 2.19-128.7) and having a second residence in the forest (aOR 6.29, 95% CI 2.29-17.31 and 13.53, 95% CI 2.10-87.12). Male forest-goers were a diverse population employed in a variety of occupations including logging, farming, and mining, sleeping in settings, such as huts, tents, and barracks, and working in a wide range of group sizes. Reported use of protective measures, such as nets, hammock nets, mosquito coils, and repellents was low among forest-goers and interventions at forest residences were absent.
CONCLUSIONS
Second residences in the forest and gaps in use of protective measures point to key malaria interventions to improve coverage in forest-going populations at risk for P. knowlesi and P. vivax in Aceh, Indonesia. Intensified strategies tailored to specific sub-populations will be essential to achieve elimination.
Topics: Male; Humans; Indonesia; Case-Control Studies; Malaria; Malaria, Vivax; Forests
PubMed: 38291392
DOI: 10.1186/s12936-024-04856-8 -
BMC Public Health Jan 2024Zoonotic malaria is a growing public health threat in the WHO Southeast Asia (SEA) and Western Pacific (WP) regions. Despite vector-control measures, the distribution of...
BACKGROUND
Zoonotic malaria is a growing public health threat in the WHO Southeast Asia (SEA) and Western Pacific (WP) regions. Despite vector-control measures, the distribution of Macaque fascicularis and M. nemestrina, and Anopheles mosquitoes carrying non-human simian malaria parasites poses challenges to malaria elimination. The systematic review assesses the literature on knowledge and malaria-preventive practices in zoonotic malaria-affected areas across the WHO SEA and WP, aiming to identify challenges for malaria control.
METHODS
Peer-reviewed articles published in English, Malay and Indonesian between January 2010 and December 2022 were searched in OVID Medline, Scopus, Web of Science, and Google Scholar. Studies of any design-excluding reviews, conference proceedings, and reports from all WHO SEA and WP countries vulnerable to zoonotic malaria-were included. Backwards-reference screening and thematic analysis were conducted.
RESULTS
Among 4,174 initially searched articles, 22 peer-reviewed articles met the inclusion criteria. An additional seven articles were identified through backwards-reference screening, resulting in a total of 29 articles for this review. Half of these studies were conducted in Cambodia, Myanmar, Malaysia, and Thailand, mainly in forests and remote communities. The review highlighted inconsistencies in the operationalization of knowledge, and five major themes were identified related to knowledge: causation and transmission, symptoms, treatment, severity and complications, and malaria prevention. While participants generally had some understanding of malaria causation/transmission, minority and indigenous ethnic groups demonstrated limited knowledge and held misconceptions, such as attributing malaria to drinking dirty water. Preventive practices included traditional and non-traditional or modern methods-with a preference for traditional approaches to avoid mosquito bites. Challenges to malaria control included feasibility, cost, and access to healthcare services.
CONCLUSION
This review provides insights into knowledge, local understandings, and preventive practices related to malaria in the WHO SEA and WP regions. The findings highlight the need for future research to explore the knowledge of at-risk communities regarding zoonotic malaria, their perceive threat of the disease and factors exposing them to zoonotic malaria. New strategies must be developed for zoonotic malaria programs tailored to local contexts, emphasizing the significance of community participation, health education, and socio-behavioural change initiatives. It is important to consider the interconnectedness of human health, environmental and non-human primates conservation. Socio-cultural nuances should also be carefully considered in the design and implementation of these programs to ensure their effect tailored to local contexts.
Topics: Animals; Humans; Antimalarials; Mosquito Vectors; Malaria; Asia, Southeastern; Cambodia
PubMed: 38287308
DOI: 10.1186/s12889-024-17792-8 -
PLoS Neglected Tropical Diseases Jan 2024Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to... (Review)
Review
BACKGROUND
Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to humans via mosquitoes of the Anopheles Leucosphyrus Group. The risk of human P. knowlesi infection varies across Southeast Asia and is dependent upon environmental factors. Understanding this geographic variation in risk is important both for enabling appropriate diagnosis and treatment of the disease and for improving the planning and evaluation of malaria elimination. However, the data available on P. knowlesi occurrence are biased towards regions with greater surveillance and sampling effort. Predicting the spatial variation in risk of P. knowlesi malaria requires methods that can both incorporate environmental risk factors and account for spatial bias in detection.
METHODS & RESULTS
We extend and apply an environmental niche modelling framework as implemented by a previous mapping study of P. knowlesi transmission risk which included data up to 2015. We reviewed the literature from October 2015 through to March 2020 and identified 264 new records of P. knowlesi, with a total of 524 occurrences included in the current study following consolidation with the 2015 study. The modelling framework used in the 2015 study was extended, with changes including the addition of new covariates to capture the effect of deforestation and urbanisation on P. knowlesi transmission.
DISCUSSION
Our map of P. knowlesi relative transmission suitability estimates that the risk posed by the pathogen is highest in Malaysia and Indonesia, with localised areas of high risk also predicted in the Greater Mekong Subregion, The Philippines and Northeast India. These results highlight areas of priority for P. knowlesi surveillance and prospective sampling to address the challenge the disease poses to malaria elimination planning.
Topics: Animals; Humans; Plasmodium knowlesi; Prospective Studies; Asia, Southeastern; Malaria; Malaysia; Macaca; Anopheles
PubMed: 38252650
DOI: 10.1371/journal.pntd.0011570 -
Royal Society Open Science Jan 2024Disease surveillance aims to collect data at different times or locations, to assist public health authorities to respond appropriately. Surveillance of the simian...
Disease surveillance aims to collect data at different times or locations, to assist public health authorities to respond appropriately. Surveillance of the simian malaria parasite, , is sparse in some endemic areas and the spatial extent of transmission is uncertain. Zoonotic transmission of has been demonstrated throughout Southeast Asia and represents a major hurdle to regional malaria elimination efforts. Given an arbitrary spatial prediction of relative disease risk, we develop a flexible framework for surveillance site selection, drawing on principles from multi-criteria decision-making. To demonstrate the utility of our framework, we apply it to the case study of malaria surveillance site selection in western Indonesia. We demonstrate how statistical predictions of relative disease risk can be quantitatively incorporated into public health decision-making, with specific application to active human surveillance of zoonotic malaria. This approach can be used in other contexts to extend the utility of modelling outputs.
PubMed: 38204787
DOI: 10.1098/rsos.230641 -
Journal of Vector Borne Diseases 2023Severe malaria is a medical emergency and can lead to severe complications and death if not treated promptly and appropriately. Along with Plasmodium falciparum, P....
BACKGROUND & OBJECTIVES
Severe malaria is a medical emergency and can lead to severe complications and death if not treated promptly and appropriately. Along with Plasmodium falciparum, P. knowlesi is increasingly recognised as a significant cause of fatal and severe malaria.
METHODS
We performed a retrospective review on 54 cases of severe malaria in a district hospital in Kapit, Sarawak, from January 2018 to May 2019. The patients' demographics, clinical features, complications based on organ involvement, and treatment outcomes were examined.
RESULTS
There were 54 cases of severe malaria, with the majority being male (70%) and between the ages of 40 and 49 (26%). All patients with severe malaria were febrile or had a history of pyrexia except for one patient. P. knowlesi (81.5%) was the most common species causing severe malaria in our study, followed by P. falciparum (13%), and P. vivax (5.5%). There were no cases of severe malaria caused by P. ovale or P. malariae. Hyperparasitaemia was present in 76% of patients and the median parasitemia value at hospital admission was 33,944 parasites/μL (interquartile range: 19,920-113,285 parasites/μL). Circulatory shock was observed in 17 patients (31.5%). There were eight patients with acute renal failure and six patients with respiratory distress. One patient died as a result of severe malaria with multiorgan involvement (1.9% fatality rate).
INTERPRETATION & CONCLUSION
P. knowlesi is the most common cause of severe malaria in Kapit, Sarawak, Malaysia. Recognizing symptoms of severe malaria and prompt administration of antimalarial are critical for good clinical outcomes.
Topics: Humans; Male; Adult; Middle Aged; Female; Malaysia; Borneo; Plasmodium knowlesi; Malaria; Antimalarials; Malaria, Vivax; Malaria, Falciparum
PubMed: 38174522
DOI: 10.4103/0972-9062.374238