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Fulltext Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia

Tobin RJ, Harrison LE, Tully MK, Lubis IND, Noviyanti R, Anstey NM, et al.

PLoS Negl Trop Dis, 2024 Jan;18(1):e0011570.
PMID: 38252650 DOI: 10.1371/journal.pntd.0011570

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.

Matched MeSH terms: Plasmodium knowlesi*
Fulltext Landscape drives zoonotic malaria prevalence in non-human primates

Johnson E, Sunil Kumar Sharma R, Ruiz Cuenca P, Byrne I, Salgado-Lynn M, Suraya Shahar Z, et al.

Elife, 2024 May 16;12.
PMID: 38753426 DOI: 10.7554/eLife.88616

Zoonotic disease dynamics in wildlife hosts are rarely quantified at macroecological scales due to the lack of systematic surveys. Non-human primates (NHPs) host Plasmodium knowlesi, a zoonotic malaria of public health concern and the main barrier to malaria elimination in Southeast Asia. Understanding of regional P. knowlesi infection dynamics in wildlife is limited. Here, we systematically assemble reports of NHP P. knowlesi and investigate geographic determinants of prevalence in reservoir species. Meta-analysis of 6322 NHPs from 148 sites reveals that prevalence is heterogeneous across Southeast Asia, with low overall prevalence and high estimates for Malaysian Borneo. We find that regions exhibiting higher prevalence in NHPs overlap with human infection hotspots. In wildlife and humans, parasite transmission is linked to land conversion and fragmentation. By assembling remote sensing data and fitting statistical models to prevalence at multiple spatial scales, we identify novel relationships between P. knowlesi in NHPs and forest fragmentation. This suggests that higher prevalence may be contingent on habitat complexity, which would begin to explain observed geographic variation in parasite burden. These findings address critical gaps in understanding regional P. knowlesi epidemiology and indicate that prevalence in simian reservoirs may be a key spatial driver of human spillover risk.

Matched MeSH terms: Plasmodium knowlesi*
Fulltext Falling Plasmodium knowlesi Malaria Death Rate among Adults despite Rising Incidence, Sabah, Malaysia, 2010-2014

Rajahram GS, Barber BE, William T, Grigg MJ, Menon J, Yeo TW, et al.

Emerg Infect Dis, 2016 Jan;22(1):41-8.
PMID: 26690736 DOI: 10.3201/eid2201.151305

Deaths from Plasmodium knowlesi malaria have been linked to delayed parenteral treatment. In Malaysia, early intravenous artesunate is now recommended for all severe malaria cases. We describe P. knowlesi fatalities in Sabah, Malaysia, during 2012-2014 and report species-specific fatality rates based on 2010-2014 case notifications. Sixteen malaria-associated deaths (caused by PCR-confirmed P. knowlesi [7], P. falciparum [7], and P. vivax [1] and microscopy-diagnosed "P. malariae" [1]) were reported during 2012-2014. Six patients with severe P. knowlesi malaria received intravenous artesunate at hospital admission. For persons ≥15 years of age, overall fatality rates during 2010-2014 were 3.4, 4.2, and 1.0 deaths/1,000 P. knowlesi, P. falciparum, and P. vivax notifications, respectively; P. knowlesi-associated fatality rates fell from 9.2 to 1.6 deaths/1,000 notifications. No P. knowlesi-associated deaths occurred among children, despite 373 notified cases. Although P. knowlesi malaria incidence is rising, the notification-fatality rate has decreased, likely due to improved use of intravenous artesunate.

Matched MeSH terms: Plasmodium knowlesi/pathogenicity*
Fulltext Evaluation of recombinant Plasmodium knowlesi merozoite surface protein-1(33) for detection of human malaria

Cheong FW, Lau YL, Fong MY, Mahmud R

Am J Trop Med Hyg, 2013 May;88(5):835-40.
PMID: 23509118 DOI: 10.4269/ajtmh.12-0250

Plasmodium knowlesi is now known as the fifth Plasmodium species that can cause human malaria. The Plasmodium merozoite surface protein (MSP) has been reported to be potential target for vaccination and diagnosis of malaria. MSP-1(33) has been shown to be immunogenic and its T cell epitopes could mediate cellular immune protection. However, limited studies have focused on P. knowlesi MSP-133. In this study, an approximately 28-kDa recombinant P. knowlesi MSP-1(33) (pkMSP-1(33)) was expressed by using an Escherichia coli system. The purified pkMSP-1(33) reacted with serum samples of patients infected with P. knowlesi (31 of 31, 100%) and non-P. knowlesi malaria (27 of 28, 96.43%) by Western blotting. The pkMSP-1(33) also reacted with P. knowlesi (25 of 31, 80.65%) and non-P. knowlesi malaria sera (20 of 28, 71.43%) in an enzyme-linked immunosorbent assay (ELISA). Most of the non-malarial infection (49 of 52 in by Western blotting and 46 of 52 in the ELISA) and healthy donor serum samples (65 of 65 by Western blotting and ELISA) did not react with recombinant pkMSP-1(33).

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/immunology; Plasmodium knowlesi/metabolism*
Fulltext Hyperparasitaemic human Plasmodium knowlesi infection with atypical morphology in peninsular Malaysia

Lee WC, Chin PW, Lau YL, Chin LC, Fong MY, Yap CJ, et al.

Malar J, 2013;12:88.
PMID: 23496970 DOI: 10.1186/1475-2875-12-88

Plasmodium knowlesi is a potentially life-threatening zoonotic malaria parasite due to its relatively short erythrocytic cycle. Microscopic identification of P. knowlesi is difficult, with "compacted parasite cytoplasm" being one of the important identifying keys. This report is about a case of hyperparasitaemic human P. knowlesi infection (27% parasitaemia) with atypical amoeboid morphology. A peninsular Malaysian was admitted to the hospital with malaria. He suffered anaemia and acute kidney function impairment. Microscopic examination, assisted by nested PCR and sequencing confirmed as P. knowlesi infection. With anti-malarial treatment and several medical interventions, patient survived and recovered. One-month medical follow-up was performed after recovery and no recrudescence was noted. This case report highlights the extreme hyperparasitaemic setting, the atypical morphology of P. knowlesi in the patient's erythrocytes, as well as the medical interventions involved in this successfully treated case.

Matched MeSH terms: Plasmodium knowlesi/cytology*; Plasmodium knowlesi/genetics; Plasmodium knowlesi/isolation & purification*
Detection of human malaria using recombinant Plasmodium knowlesi merozoire surface protein-1 (MSP-1₁₉) expressed in Escherichia coli

Sonaimuthu P, Cheong FW, Chin LC, Mahmud R, Fong MY, Lau YL

Exp Parasitol, 2015 Jun;153:118-22.
PMID: 25812552 DOI: 10.1016/j.exppara.2015.03.010

Malaria remains one of the world's most important infectious diseases and is responsible for enormous mortality and morbidity. Human infection with Plasmodium knowlesi is widely distributed in Southeast Asia. Merozoite surface protein-1₁₉ (MSP-1₁₉), which plays an important role in protective immunity against asexual blood stage malaria parasites, appears as a leading immunogenic antigen of Plasmodium sp. We evaluated the sensitivity and specificity of recombinant P. knowlesi MSP-1₁₉ (rMSP-1₁₉) for detection of malarial infection. rMSP-1₁₉ was expressed in Escherichia coli expression system and the purified rMSP-1₁₉ was evaluated with malaria, non-malaria and healthy human serum samples (n = 215) in immunoblots. The sensitivity of rMSP-1₁₉ for detection of P. knowlesi, Plasmodium falciparum, Plasmodium vivax and Plasmodium ovale infection was 95.5%, 75.0%, 85.7% and 100%, respectively. rMSP-1₁₉ did not react with all the non-malaria and healthy donor sera, which represents 100% specificity. The rMSP-1₁₉ could be used as a potential antigen in serodiagnosis of malarial infection in humans.

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/isolation & purification; Plasmodium knowlesi/metabolism*
Fulltext A five-year retrospective review on malaria incidence and profile in Malaysia, 2013 – 2017

Narwani Hussin, Yvonne Ai Lian Lim, Pik Pin Goh, Timothy William, Jenarun Jelip, Rose Nani Mudin

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):45-45.
MyJurnal

Introduction: Most of the recent publications on malaria in Malaysia were conducted in Sabah focusing on the emer-gence of Plasmodium knowlesi. This analysis aims to look into the incidence, mortality, and case fatality rate (CFR) of malaria caused by all Plasmodium species in the whole of Malaysia and to compare the different malaria char-acteristics and trends between Peninsular Malaysia (PM) and Sabah & Sarawak. Methods: This is a secondary data review of all malaria confirmed cases notified to the Ministry of Health, Malaysia from January 2013 to December 2017. Results: From 2013 to 2017, a total of 16,500 malaria cases were notified in Malaysia. The cases were mainly contributed from Sabah (7,150; 43.3%) and Sarawak (5,684; 34.4%). Plasmodium knowlesi was the commonest species in Sabah and Sarawak (9,902; 77.1%), while there were more Plasmodium vivax cases (1,548; 42.2%) in PM. The overall average incidence rates (IR), mortality rate (MR) and CFR for malaria in Malaysia were 0.106/1,000, 0.030/100,000 and 0.27%, respectively. Sarawak reported the highest average IR of 0.420/1,000 followed by Sabah (0.383/1,000). Other states in PM reported below the national average IR with

Matched MeSH terms: Plasmodium knowlesi
Fulltext Molecular epidemiology of the emerging human malaria parasite "Plasmodium knowlesi"

Hakimi H, Kawai S, Kawazu S

Trop Parasitol, 2014 Jan;4(1):20-4.
PMID: 24754022 DOI: 10.4103/2229-5070.129154

Malaria is the most important parasitic disease with global concern. Plasmodium knowlesi recently has emerged from its natural simian host as a significant cause of human malaria, particularly in Malaysian Borneo. Therefore, it has been added as the fifth human Plasmodium specie which is widely distributed in Southeast Asia. Recent developments of new molecular tools enhanced our understanding about the key features of this malaria parasite. Here, we review some of the ways in which molecular approaches might be used for epidemiology of P. knowlesi and finally lead to an efficient control of malaria.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Sequence analysis on the mitochondrial COXI gene of recent clinical isolates of Plasmodium knowlesi in Klang Valley, peninsular Malaysia

Fong MY, Lau YL, Chin LC, Al-Mekhlafi AM

Trop Biomed, 2011 Aug;28(2):457-63.
PMID: 22041769

The cytochrome oxidase subunit I (COXI) gene sequences of three recent (2007-2008) clinical Plasmodium knowlesi isolates from Klang Valley, peninsular Malaysia, were determined and compared with those of older (1960's) peninsular Malaysia, recent isolates from Sarawak (on Borneo Island), and an isolate from Thailand. Multiple alignment of the sequences showed that the three clinical isolates were more similar to the older peninsular Malaysia isolates than to those from Sarawak and Thailand. Phylogenetic tree based on the COXI sequences revealed three distinct clusters of P. knowlesi. The first cluster consisted of isolates from peninsular Malaysia, the second consisted of Sarawak isolates and the third composed of the Thailand isolate. The findings of this study highlight the usefulness of mitochondrial COXI gene as a suitable marker for phylogeographic studies of P. knowlesi.

Matched MeSH terms: Plasmodium knowlesi/enzymology*; Plasmodium knowlesi/genetics*; Plasmodium knowlesi/isolation & purification
Fulltext Increased detection of Plasmodium knowlesi in Sandakan division, Sabah as revealed by PlasmoNex™

Goh XT, Lim YA, Vythilingam I, Chew CH, Lee PC, Ngui R, et al.

Malar J, 2013 Jul 31;12:264.
PMID: 23902626 DOI: 10.1186/1475-2875-12-264

BACKGROUND: Plasmodium knowlesi is a simian malaria parasite that is widespread in humans in Malaysian Borneo. However, little is known about the incidence and distribution of this parasite in the Sandakan division, Malaysian Borneo. Therefore, the aim of the present epidemiological study was to investigate the incidence and distribution of P. knowlesi as well as other Plasmodium species in this division based on a most recent developed hexaplex PCR system (PlasmoNex™).
METHODS: A total of 189 whole blood samples were collected from Telupid Health Clinic, Sabah, Malaysia, from 2008 to 2011. All patients who participated in the study were microscopically malaria positive before recruitment. Complete demographic details and haematological profiles were obtained from 85 patients (13 females and 72 males). Identification of Plasmodium species was conducted using PlasmoNex™ targeting the 18S ssu rRNA gene.
RESULTS: A total of 178 samples were positive for Plasmodium species by using PlasmoNex™. Plasmodium falciparum was identified in 68 samples (38.2%) followed by 64 cases (36.0%) of Plasmodium vivax, 42 (23.6%) cases of P. knowlesi, two (1.1%) cases of Plasmodium malariae and two (1.1%) mixed-species infections (i e, P. vivax/P. falciparum). Thirty-five PlasmoNex™ positive P. knowlesi samples were misdiagnosed as P. malariae by microscopy. Plasmodium knowlesi was detected in all four districts of Sandakan division with the highest incidence in the Kinabatangan district. Thrombocytopaenia and anaemia showed to be the most frequent malaria-associated haematological complications in this study.
CONCLUSIONS: The discovery of P. knowlesi in Sandakan division showed that prospective studies on the epidemiological risk factors and transmission dynamics of P. knowlesi in these areas are crucial in order to develop strategies for effective malaria control. The availability of advanced diagnostic tool PlasmoNex™ enhanced the accuracy and accelerated the speed in the diagnosis of malaria.

Matched MeSH terms: Plasmodium knowlesi/classification; Plasmodium knowlesi/genetics; Plasmodium knowlesi/isolation & purification*
Fulltext Genetic diversity, haplotypes and allele groups of Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from Peninsular Malaysia

Fong MY, Lau YL, Chang PY, Anthony CN

Parasit Vectors, 2014;7:161.
PMID: 24693997 DOI: 10.1186/1756-3305-7-161

The monkey malaria parasite Plasmodium knowlesi is now recognized as the fifth species of Plasmodium that can cause human malaria. Like the region II of the Duffy binding protein of P. vivax (PvDBPII), the region II of the P. knowlesi Duffy binding protein (PkDBPαII) plays an essential role in the parasite's invasion into the host's erythrocyte. Numerous polymorphism studies have been carried out on PvDBPII, but none has been reported on PkDBPαII. In this study, the genetic diversity, haplotyes and allele groups of PkDBPαII of P. knowlesi clinical isolates from Peninsular Malaysia were investigated.

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/metabolism*
Fulltext First case of detection of Plasmodium knowlesi in Spain by Real Time PCR in a traveller from Southeast Asia

Ta TT, Salas A, Ali-Tammam M, Martínez Mdel C, Lanza M, Arroyo E, et al.

Malar J, 2010;9:219.
PMID: 20663184 DOI: 10.1186/1475-2875-9-219

Previously, Plasmodium knowlesi was not considered as a species of Plasmodium that could cause malaria in human beings, as it is parasite of long-tailed (Macaca fascicularis) and pig-tailed (Macaca nemestrina) macaques found in Southeast Asia. A case of infection by P. knowlesi is described in a Spanish traveller, who came back to Spain with daily fever after his last overseas travel, which was a six-month holiday in forested areas of Southeast Asia between 2008 and 2009. His P. knowlesi infection was detected by multiplex Real time quantitative PCR and confirmed by sequencing the amplified fragment. Using nested multiplex malaria PCR (reference method in Spain) and a rapid diagnostic test, the P. knowlesi infection was negative. This patient was discharged and asymptomatic when the positive result to P. knowlesi was reported. Prior to this case, there have been two more reports of European travellers with malaria caused by P. knowlesi, a Finnish man who travelled to Peninsular Malaysia during four weeks in March 2007, and a Swedish man who did a short visit to Malaysian Borneo in October 2006. Taken together with this report of P. knowlesi infection in a Spanish traveller returning from Southeast Asia, this is the third case of P. knowlesi infection in Europe, indicating that this simian parasite can infect visitors to endemic areas in Southeast Asia. This last European case is quite surprising, given that it is an untreated-symptomatic P. knowlesi in human, in contrast to what is currently known about P. knowlesi infection. Most previous reports of human P. knowlesi malaria infections were in adults, often with symptoms and relatively high parasite densities, up to the recent report in Ninh Thuan province, located in the southern part of central Vietnam, inhabited mainly by the Ra-glai ethnic minority, in which all P. knowlesi infections were asymptomatic, co-infected with P. malariae, with low parasite densities and two of the three identified cases were very young children under five years old.

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/isolation & purification*
Fulltext Plasmodium knowlesi malaria in Vietnam: some clarifications

Van den Eede P, Vythilingam I, Ngo DT, Nguyen VH, Le XH, D'Alessandro U, et al.

Malar J, 2010;9:20.
PMID: 20082717 DOI: 10.1186/1475-2875-9-20

A recently published comment on a report of Plasmodium knowlesi infections in Vietnam states that this may not accurately represent the situation in the study area because the PCR primers used may cross-hybridize with Plasmodium vivax. Nevertheless, P. knowlesi infections have been confirmed by sequencing. In addition, a neighbour-joining tree based on the 18S S-Type SSUrRNA gene shows that the Vietnamese samples clearly cluster with the P. knowlesi isolates identified in Malaysia and are distinct from the corresponding P. vivax sequences. All samples came from asymptomatic individuals who did not consult for fever during the months preceding or following the survey, indicating that asymptomatic P. knowlesi infections occur in this population, although this does not exclude the occurrence of symptomatic cases. Large-scale studies to determine the extent and the epidemiology of P. knowlesi malaria in Vietnam are further needed.

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/isolation & purification*
Natural transmission of Plasmodium knowlesi to humans by Anopheles latens in Sarawak, Malaysia

Vythilingam I, Tan CH, Asmad M, Chan ST, Lee KS, Singh B

Trans R Soc Trop Med Hyg, 2006 Nov;100(11):1087-8.
PMID: 16725166

Four species of malaria parasites are known to infect humans. A fifth species, Plasmodium knowlesi, has been reported to infect humans in Malaysian Borneo. Here we report for the first time the incrimination of Anopheles latens as the vector of P. knowlesi among humans and monkeys in Sarawak, Malaysia.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification; Plasmodium knowlesi/pathogenicity*
Genetic polymorphism in domain I of the apical membrane antigen-1 among Plasmodium knowlesi clinical isolates from Peninsular Malaysia

Fong MY, Wong SS, Silva JR, Lau YL

Acta Trop, 2015 Dec;152:145-150.
PMID: 26384455 DOI: 10.1016/j.actatropica.2015.09.009

The simian malaria parasite Plasmodium knowlesi is now recognized as a species that can cause human malaria. The first report of large scale human knowlesi malaria was in 2004 in Malaysia Borneo. Since then, hundreds of human knowlesi malaria cases have been reported in Southeast Asia. The present study investigates the genetic polymorphism of P. knowlesi DI domain of the apical membrane antigen-1 (AMA-1), a protein considered as a promising vaccine candidate for malaria. The DI domain of AMA-1 gene of P. knowlesi clinical isolates from Peninsular Malaysia was amplified by PCR, cloned into Escherichia coli, then sequenced and analysed. Ninety-seven DI domain sequences were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence showed 21 synonymous and 25 nonsynonymous mutations. Nonetheless, nucleotide sequence analysis revealed low genetic diversity of the DI domain, and it was under purifying (negative) selection. At the amino acid level, 26 different haplotypes were identified and 2 were predominant haplotypes (H1, H2) with high frequencies. Phylogenetic analysis revealed that the 26 haplotypes could be clustered into 2 distinct groups (I and II). Members of the groups were basically derived from haplotypes H1 and H2, respectively.

Matched MeSH terms: Plasmodium knowlesi/classification; Plasmodium knowlesi/genetics*
Fulltext Case Report: Case Series of Human Plasmodium knowlesi Infection on the Southern Border of Thailand

Ngernna S, Rachaphaew N, Thammapalo S, Prikchoo P, Kaewnah O, Manopwisedjaroen K, et al.

Am J Trop Med Hyg, 2019 12;101(6):1397-1401.
PMID: 31595871 DOI: 10.4269/ajtmh.19-0063

Although human infections of Plasmodium knowlesi have been found throughout Southeast Asia, most cases originated from Malaysian Borneo. In Thailand, P. knowlesi malaria was considered extremely rare. However, during October 2017-September 2018, there was a surge in the number of reported P. knowlesi cases. Here, a series of six cases of P. knowlesi malaria found during this period in Songkhla and Narathiwat provinces of southern Thailand are presented. All cases were confirmed by polymerase chain reaction. The unprecedented case number in the affected area is a warning sign of an increasing P. knowlesi burden in the south of Thailand.

Matched MeSH terms: Plasmodium knowlesi/drug effects; Plasmodium knowlesi/pathogenicity*
Fulltext Low Levels of Polymorphisms and Negative Selection in Plasmodum knowlesi Merozoite Surface Protein 8 in Malaysian Isolates

Atique Ahmed M, Kang HJ, Quan FS

Korean J Parasitol, 2019 Aug;57(4):445-450.
PMID: 31533414 DOI: 10.3347/kjp.2019.57.4.445

Human infections due to the monkey malaria parasite Plasmodium knowlesi is increasingly being reported from most Southeast Asian countries specifically Malaysia. The parasite causes severe and fatal malaria thus there is a need for urgent measures for its control. In this study, the level of polymorphisms, haplotypes and natural selection of full-length pkmsp8 in 37 clinical samples from Malaysian Borneo along with 6 lab-adapted strains were investigated. Low levels of polymorphism were observed across the full-length gene, the double epidermal growth factor (EGF) domains were mostly conserved, and non-synonymous substitutions were absent. Evidence of strong negative selection pressure in the non-EGF regions were found indicating functional constrains acting at different domains. Phylogenetic haplotype network analysis identified shared haplotypes and indicated geographical clustering of samples originating from Peninsular Malaysia and Malaysian Borneo. This is the first study to genetically characterize the full-length msp8 gene from clinical isolates of P. knowlesi from Malaysia; however, further functional characterization would be useful for future rational vaccine design.

Matched MeSH terms: Plasmodium knowlesi/genetics*; Plasmodium knowlesi/immunology
Indel-informed Bayesian analysis suggests cryptic population structure between Plasmodium knowlesi of humans and long-tailed macaques (Macaca fascicularis) in Malaysian Borneo

Wilcox JS, Kerschner A, Hollocher H

Infect Genet Evol, 2019 11;75:103994.
PMID: 31421245 DOI: 10.1016/j.meegid.2019.103994

Plasmodium knowlesi is an important causative agent of malaria in humans of Southeast Asia. Macaques are natural hosts for this parasite, but little is conclusively known about its patterns of transmission within and between these hosts. Here, we apply a comprehensive phylogenetic approach to test for patterns of cryptic population genetic structure between P. knowlesi isolated from humans and long-tailed macaques from the state of Sarawak in Malaysian Borneo. Our approach differs from previous investigations through our exhaustive use of archival 18S Small Subunit rRNA (18S) gene sequences from Plasmodium and Hepatocystis species, our inclusion of insertion and deletion information during phylogenetic inference, and our application of Bayesian phylogenetic inference to this problem. We report distinct clades of P. knowlesi that predominantly contained sequences from either human or macaque hosts for paralogous A-type and S-type 18S gene loci. We report significant partitioning of sequence distances between host species across both types of loci, and confirmed that sequences of the same locus type showed significantly biased assortment into different clades depending on their host species. Our results support the zoonotic potential of Plasmodium knowlesi, but also suggest that humans may be preferentially infected with certain strains of this parasite. Broadly, such patterns could arise through preferential zoonotic transmission of some parasite lineages or a disposition of parasites to transmit within, rather than between, human and macaque hosts. Available data are insufficient to address these hypotheses. Our results suggest that the epidemiology of P. knowlesi may be more complicated than previously assumed, and highlight the need for renewed and more vigorous explorations of transmission patterns in the fifth human malarial parasite.

Matched MeSH terms: Plasmodium knowlesi/classification*; Plasmodium knowlesi/genetics
Fulltext Identification of Plasmodium knowlesi Merozoite Surface Protein-119 (PkMSP-119 ) novel binding peptides from a phage display library

Goh XT, Chua KH, Kee BP, Lim YAL

Trop Med Int Health, 2020 02;25(2):172-185.
PMID: 31733137 DOI: 10.1111/tmi.13348

OBJECTIVE: Plasmodium knowlesi, the fifth human malaria parasite, has caused mortality in humans. We aimed to identify P. knowlesi novel binding peptides through a random linear dodecapeptide phage display targeting the 19-kDa fragment of Merozoite Surface Protein-1 protein.
METHODS: rPkMSP-119 protein was heterologously expressed using Expresso® Solubility and Expression Screening System and competent E. cloni® 10G cells according to protocol. Three rounds of biopanning were performed on purified rPkMSP-119 to identify binding peptides towards rPkMSP-119 using Ph.D.™-12 random phage display library. Binding sites of the identified peptides to PkMSP-119 were in silico predicted using the CABS-dock web server.
RESULTS: Four phage peptide variants that bound to PkMSP-119 were identified after three rounds of biopanning, namely Pkd1, Pkd2, Pkd3 and Pkd4. The sequences of both Pkd1 and Pkd2 consist of a large number of histidine residues. Pkd1 showed positive binding signal with 6.1× vs. BSA control. Docking results showed that Pkd1 and Pkd2 were ideal binding peptides for PkMSP-119 .
CONCLUSION: We identified two novel binding peptides of PkMSP-119 , Pkd1 (HFPFHHHKLRAH) and Pkd2 (HPMHMLHKRQHG), through phage display. They provide a valuable starting point for the development of novel therapeutics.

Matched MeSH terms: Plasmodium knowlesi/genetics*; Plasmodium knowlesi/metabolism*
Genetic diversity in the C-terminus of merozoite surface protein 1 among Plasmodium knowlesi isolates from Selangor and Sabah Borneo, Malaysia

Yap NJ, Goh XT, Koehler AV, William T, Yeo TW, Vythilingam I, et al.

Infect Genet Evol, 2017 10;54:39-46.
PMID: 28634105 DOI: 10.1016/j.meegid.2017.06.019

Plasmodium knowlesi, a malaria parasite of macaques, has emerged as an important parasite of humans. Despite the significance of P. knowlesi malaria in parts of Southeast Asia, very little is known about the genetic variation in this parasite. Our aim here was to explore sequence variation in a molecule called the 42kDa merozoite surface protein-1 (MSP-1), which is found on the surface of blood stages of Plasmodium spp. and plays a key role in erythrocyte invasion. Several studies of P. falciparum have reported that the C-terminus (a 42kDa fragment) of merozoite surface protein-1 (MSP-142; consisting of MSP-119 and MSP-133) is a potential candidate for a malaria vaccine. However, to date, no study has yet investigated the sequence diversity of the gene encoding P. knowlesi MSP-142 (comprising Pk-msp-119 and Pk-msp-133) among isolates in Malaysia. The present study explored this aspect. Twelve P. knowlesi isolates were collected from patients from hospitals in Selangor and Sabah Borneo, Malaysia, between 2012 and 2014. The Pk-msp-142 gene was amplified by PCR and directly sequenced. Haplotype diversity (Hd) and nucleotide diversity (л) were studied among the isolates. There was relatively high genetic variation among P. knowlesi isolates; overall Hd and л were 1±0.034 and 0.01132±0.00124, respectively. A total of nine different haplotypes related to amino acid alterations at 13 positions, and the Pk-MSP-119 sequence was found to be more conserved than Pk-msp-133. We have found evidence for negative selection in Pk-msp-42 as well as the 33kDa and 19kDa fragments by comparing the rate of non-synonymous versus synonymous substitutions. Future investigations should study large numbers of samples from disparate geographical locations to critically assess whether this molecule might be a potential vaccine target for P. knowlesi.

Matched MeSH terms: Plasmodium knowlesi/classification; Plasmodium knowlesi/genetics*

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