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Plasmodium knowlesi - an emerging pathogen

Ahmed MA, Cox-Singh J

ISBT science series, 2015 Apr;10(Suppl 1):134-140.
PMID: 26029250

Ten years have passed since the publication of a large focus of Plasmodium knowlesi infections in the human population. The discovery was made during a molecular investigation of atypical P. malariae cases in the Kapit Health Division, Sarawak, Malaysian Borneo. Patients were more symptomatic with higher parasite counts than expected in P. malariae infections. The investigation found only P. knowlesi DNA present in patient blood samples. Morphological similarity had allowed P. knowlesi to masquerade as P. malariae during routine diagnostic microscopy for malaria. P. knowlesi, a malaria parasite of macaque monkeys, had entered the human population. The subsequent development of P. knowlesi species-specific PCR assays soon demonstrated that the entry was not confined to the Kapit Division but extended across island and mainland Southeast Asia. Relevant clinical descriptions and guidelines for the treatment and management of patents with P. knowlesi malaria were not available. Nor was it clear whether P. knowlesi had undergone a host switch event into the human population or if infections were zoonotic. The outputs of studies on P. knowlesi malaria during the past 10 years will be summarized, highlighting major findings within the context of pathophysiology, virulence, host switch events, treatment, control and importantly malaria elimination.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Human infections with Plasmodium knowlesi--zoonotic malaria

Millar SB, Cox-Singh J

Clin Microbiol Infect, 2015 Jul;21(7):640-8.
PMID: 25843504 DOI: 10.1016/j.cmi.2015.03.017

In 2004 a large focus of Plasmodium knowlesi malaria was reported in the human population in Sarawak, Malaysian Borneo. Plasmodium knowlesi, a parasite of the South-East Asian macaques (Macaca fascicularis and Macaca nemestrina), had entered the human population. Plasmodium knowlesi is transmitted by the leucosphyrus group of Anopheline mosquitoes and transmission is largely zoonotic and restricted to the jungle setting. Humans entering jungle transmission sites are at risk. Since 2004, human cases of P. knowlesi have been continuously reported in local communities and in travellers returning from South East Asia. Plasmodium knowlesi is the most common type of indigenous malaria reported in Malaysia. Infections are most often uncomplicated but at least 10% of patients report with severe malaria and 1-2% of cases have a fatal outcome. Parasitaemia is positively associated with the clinical and laboratory markers of severe malaria. The current literature on P. knowlesi, including epidemiology, natural hosts and vectors, pathogenesis, clinical descriptions, treatment and diagnosis, is reviewed. There are many gaps in our understanding of this disease that are highlighted here with suggestions for further research to inform pre-emptive control measures that would be required to prevent a full emergence of this parasite into the human population.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Reassessment of the catalytic activity and substrate specificity of fkbp35 from plasmodium knowlesi using protease-free assay

Cahyo Budiman, Carlmond Goh Kah Wun, Lee, Ping Chin, Rafida Razali, Thean, Chor Leow

Borneo International Journal of Biotechnology, 2020;1(1):125-143.
MyJurnal

FK506-binding protein35 of Plasmodium knowlesi (Pk-FKBP35) is a member of peptidyl prolyl cis-trans isomerase (PPIase) and is considered as a promising avenue of antimalarial drug target development. This protein is organized into the N-terminal domain responsible for PPIase catalytic activity followed and the tetratricopeptide repeat domain for its dimerization. The protease-coupling and protease-free assays are known to be the common methods for investigating the catalytic properties of PPIase. Earlier, the protease-coupling assay was used to confirm the catalytic activity of Pk-FKBP35 in accelerating cis-trans isomerization of the peptide substrate. This report is aimed to re-assess the catalytic and substrate specificity of Pk-FKBP35 using an alternative method of a protease-free assay. The result indicated that while Pk-FKBP35 theoretically contained many possible cleavage sites of chymotrypsin, experimentally, the catalytic domain was relatively stable from chymotrypsin. Furthermore, under protease-free assay, Pk-FKBP35 also demonstrated remarkable PPIase catalytic activity with kcat/KM of 4.5 + 0.13 × 105 M−1 s−1, while the kcat/KM of active site mutant of D55A is 0.81 + 0.05 × 105 M−1 s−1. These values were considered comparable to kcat/KM obtained from the protease-coupling assay. Interestingly, the substrate specificities of Pk-FKBP35 obtained from both methods are also similar, with the preference of Pk-FKBP35 towards Xaa at P1 position was Leu>Phe>Lys>Trp>Val>Ile>His>Asp>Ala>Gln>Glu. Altogether, we proposed that protease-free and protease-coupling assays arereliable for Pk-FKBP35.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Occupationally Acquired Plasmodium knowlesi Malaria in Brunei Darussalam

Koh GJ, Ismail PK, Koh D

Saf Health Work, 2019 Mar;10(1):122-124.
PMID: 30949391 DOI: 10.1016/j.shaw.2018.09.002

Simian malaria is a zoonotic disease caused by Plasmodium knowlesi infection. The common natural reservoir of the parasite is the macaque monkey and the vector is the Anopheles mosquito. Human cases of P. knowlesi infection has been reported in all South East Asian countries in the last decade, and it is currently the most common type of malaria seen in Malaysia and Brunei. Between 2007-2017, 73 cases of P. knowlesi infection were notified and confirmed to the Ministry of Health in Brunei. Of these, 15 cases (21%) were documented as work-related, and 28 other cases (38%) were classified as probably related to work (due to incomplete history). The occupations of those with probable and confirmed work related infections were border patrol officers, Armed Forces and security personnel, Department of Forestry officers, boatmen and researchers. The remaining cases classified as most likely not related to work were possibly acquired via peri-domestic transmission. The risk of this zoonotic infection extends to tourists and overseas visitors who have to travel to the jungle in the course of their work. It can be minimised with the recommended use of prophylaxis for those going on duty into the jungles, application of mosquito/insect repellants, and use of repellant impregnated uniforms and bed nets in jungle camp sites.

Matched MeSH terms: Plasmodium knowlesi
Plasmodium knowlesi-mediated zoonotic malaria: A challenge for elimination

Naik DG

Trop Parasitol, 2020 05 20;10(1):3-6.
PMID: 32775284 DOI: 10.4103/tp.TP_17_18

Malaria, a mosquito-transmitted parasitic disease, has been targeted for elimination in many parts of the world. For many years, Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and Plasmodium malariae have been known to cause malaria in humans. Now, Plasmodium knowlesi is considered to be an important cause of malaria, especially in Southeast Asia. The emergence of P. knowlesi with zoonotic implication is a challenge in the elimination efforts of malaria in Southeast Asia. P. knowlesi is known to cause severe complicated malaria in humans. P. knowlesi parasite is transmitted between humans and wild macaque through mosquito vectors. It appears that the malaria disease severity and host immune evasion depend on antigenic variation exhibited at the surface of the infected erythrocyte. P. knowlesi is sensitive to antimalarial drug artemisinin. Identification of vector species, their biting behavior, timely correct diagnosis, and treatment are important steps in disease management and control. There is a need to identify and implement effective intervention measures to cut the chain of transmissions from animals to humans. The zoonotic malaria definitely poses a significant challenge in elimination and subsequent eradication of all types of malaria from this globe.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Host and environmental factors that influence Plasmodiu Knowlesi Mamlaria infection in humans: a systematic review

Michal Christina Steven

Borneo Epidemiology Journal, 2020;1(2):104-115.
MyJurnal

Introduction:Plasmodium knowlesi(P.knowlesi) is a zoonotic malaria parasite, transmitted between non-factors” or “individual factors” or “ecological factors” and “P.knowlesi” and “human” including human primate hosts by the Anopheles (An.) mosquitos, and causing spill-over infections in humans where the parasite, vector, host, and human converge
Methods:The search was done electronically toexplore for appropriate papers viaPubMed, and Science Direct for articles published up to March 2020, containing the words “factors associated” or “environmental synonyms and Medical Subject Heading (MeSH) terms. A total of 27 articles from PubMed Databases and 18 articles from Science Direct were selected to be assessed for eligibility. Out of it, a total of 13 articles were selected to be analysed.
Results:Host factors such as sex and age, as well as occupation as individual factors, while environmental factors such as rainfall and geographic elevation have some association with P.knowlesiinfection in humans. This zoonotic malaria poses unique challenges that will need to be addressed if all forms of malaria are to be eliminated based on the sustainable development goal (SDG)
Conclusion:This article highlights the importance of disease ecologies such as climate and landscape and human-environment interactions such as the land use patterns, such as agriculture or infrastructure activities) to reduce the further increase of cases and mortality globally due to P.knowlesiinfection. This review focuses mainly on the host and environmental factors that influence P.knowlesiMalaria Infection in Humans

Matched MeSH terms: Plasmodium knowlesi
Diversity and natural selection of Merozoite surface Protein-1 in three species of human malaria parasites: Contribution from South-East Asian isolates

Goh XT, Lim YAL, Lee PC, Nissapatorn V, Chua KH

Mol Biochem Parasitol, 2021 07;244:111390.
PMID: 34087264 DOI: 10.1016/j.molbiopara.2021.111390

The present study aimed to examine the genetic diversity of human malaria parasites (i.e., P. falciparum, P. vivax and P. knowlesi) in Malaysia and southern Thailand targeting the 19-kDa C-terminal region of Merozoite Surface Protein-1 (MSP-119). This region is essential for the recognition and invasion of erythrocytes and it is considered one of the leading candidates for asexual blood stage vaccines. However, the genetic data of MSP-119 among human malaria parasites in Malaysia is limited and there is also a need to update the current sequence diversity of this gene region among the Thailand isolates. In this study, genomic DNA was extracted from 384 microscopy-positive blood samples collected from patients who attended the hospitals or clinics in Malaysia and malaria clinics in Thailand from the year 2008 to 2016. The MSP-119 was amplified using PCR followed by bidirectional sequencing. DNA sequences identified in the present study were subjected to Median-joining network analysis with sequences of MSP-119 obtained from GenBank. DNA sequence analysis revealed that PfMSP-119 of Malaysian and Thailand isolates was not genetically conserved as high number of haplotypes were detected and positive selection was prevalent in PfMSP-119, hence questioning its suitability to be used as a vaccine candidate. A novel haplotype (Q/TNG/L) was also detected in Thailand P. falciparum isolate. In contrast, PvMSP-119 was highly conserved, however for the first time, a non-synonymous substitution (A1657S) was reported among Malaysian isolates. As for PkMSP-119, the presence of purifying selection and low nucleotide diversity indicated that it might be a potential vaccine target for P. knowlesi.

Matched MeSH terms: Plasmodium knowlesi/genetics; Plasmodium knowlesi/growth & development*; Plasmodium knowlesi/metabolism
Fulltext Detection of malaria parasites in Sabah by nested polymerase chain reaction: a focus of naturally acquired Plasmodium knowlesi infections

Anderios F, Zulaikah Mohamed, Ratnam S, Mohd Yusof Ibrahim, Tajul Ariffin Mohd Awang

Sains Malaysiana, 2008;37(2).

The emergence of primate malaria known as Plasmodium knowlesi in humans, which is always misdiagnosed by microscopy as P. malariae, has contribute to the needs of nucleic acid based technology to be applied in detection and differentiation of malaria parasites. The target DNA sequence of the 18SrRNA gene was amplified by a nested PCR assay for detection and identification of Plasmodium species in 31 Giemsa-stained blood smears examined as P. malariae. The assay demonstrated three samples identified as positive to genus-specific primers but negative to all species-specific primers. Three cases of misdiagnosed species were detected. The samples were diagnosed as P. malariae microscopically, but detected as P. falciparum by PCR assay. Twenty five out of 31 samples were detected as P. knowlesi. None of the samples diagnosed microscopically as P. malariae were identified as P. malariae with the nested PCR assay. Over 80.6% of all malaria cases in this study showed naturally acquired P. knowlesi infections.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Efficient Surveillance of Plasmodium knowlesi Genetic Subpopulations, Malaysian Borneo, 2000-2018

Divis PCS, Hu TH, Kadir KA, Mohammad DSA, Hii KC, Daneshvar C, et al.

Emerg Infect Dis, 2020 07;26(7):1392-1398.
PMID: 32568035 DOI: 10.3201/eid2607.190924

Population genetic analysis revealed that Plasmodium knowlesi infections in Malaysian Borneo are caused by 2 divergent parasites associated with long-tailed (cluster 1) and pig-tailed (cluster 2) macaques. Because the transmission ecology is likely to differ for each macaque species, we developed a simple genotyping PCR to efficiently distinguish between and survey the 2 parasite subpopulations. This assay confirmed differences in the relative proportions in areas of Kapit division of Sarawak state, consistent with multilocus microsatellite analyses. Analyses of 1,204 human infections at Kapit Hospital showed that cluster 1 caused approximately two thirds of cases with no significant temporal changes from 2000 to 2018. We observed an apparent increase in overall numbers in the most recent 2 years studied, driven mainly by increased cluster 1 parasite infections. Continued monitoring of the frequency of different parasite subpopulations and correlation with environmental alterations are necessary to determine whether the epidemiology will change substantially.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Naturally Acquired Human Plasmodium cynomolgi and P. knowlesi Infections, Malaysian Borneo

Raja TN, Hu TH, Kadir KA, Mohamad DSA, Rosli N, Wong LL, et al.

Emerg Infect Dis, 2020 08;26(8):1801-1809.
PMID: 32687020 DOI: 10.3201/eid2608.200343

To monitor the incidence of Plasmodium knowlesi infections and determine whether other simian malaria parasites are being transmitted to humans, we examined 1,047 blood samples from patients with malaria at Kapit Hospital in Kapit, Malaysia, during June 24, 2013-December 31, 2017. Using nested PCR assays, we found 845 (80.6%) patients had either P. knowlesi monoinfection (n = 815) or co-infection with other Plasmodium species (n = 30). We noted the annual number of these zoonotic infections increased greatly in 2017 (n = 284). We identified 6 patients, 17-65 years of age, with P. cynomolgi and P. knowlesi co-infections, confirmed by phylogenetic analyses of the Plasmodium cytochrome c oxidase subunit 1 gene sequences. P. knowlesi continues to be a public health concern in the Kapit Division of Sarawak, Malaysian Borneo. In addition, another simian malaria parasite, P. cynomolgi, also is an emerging cause of malaria in humans.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Population Genomic Structure and Recent Evolution of Plasmodium knowlesi, Peninsular Malaysia

Hocking SE, Divis PCS, Kadir KA, Singh B, Conway DJ

Emerg Infect Dis, 2020 08;26(8):1749-1758.
PMID: 32687018 DOI: 10.3201/eid2608.190864

Most malaria in Malaysia is caused by Plasmodium knowlesi parasites through zoonotic infection from macaque reservoir hosts. We obtained genome sequences from 28 clinical infections in Peninsular Malaysia to clarify the emerging parasite population structure and test for evidence of recent adaptation. The parasites all belonged to a major genetic population of P. knowlesi (cluster 3) with high genomewide divergence from populations occurring in Borneo (clusters 1 and 2). We also observed unexpected local genetic subdivision; most parasites belonged to 2 subpopulations sharing a high level of diversity except at particular genomic regions, the largest being a region of chromosome 12, which showed evidence of recent directional selection. Surprisingly, we observed a third subpopulation comprising P. knowlesi infections that were almost identical to each other throughout much of the genome, indicating separately maintained transmission and recent genetic isolation. Each subpopulation could evolve and present a broader health challenge in Asia.

Matched MeSH terms: Plasmodium knowlesi
Fulltext Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial

Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, et al.

Lancet Infect Dis, 2016 Feb;16(2):180-188.
PMID: 26603174 DOI: 10.1016/S1473-3099(15)00415-6

BACKGROUND: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children.
METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.
FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.
INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.
FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

Matched MeSH terms: Plasmodium knowlesi/drug effects*
Fulltext Evaluation of three rapid diagnostic tests for the detection of human infections with Plasmodium knowlesi

Foster D, Cox-Singh J, Mohamad DS, Krishna S, Chin PP, Singh B

Malar J, 2014;13:60.
PMID: 24548805 DOI: 10.1186/1475-2875-13-60

Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, infects humans and can cause fatal malaria. It is difficult to diagnose by microscopy because of morphological similarity to Plasmodium malariae. Nested PCR assay is the most accurate method to distinguish P. knowlesi from other Plasmodium species but is not cost effective in resource-poor settings. Rapid diagnostic tests (RDTs) are recommended for settings where malaria is prevalent. In this study, the effectiveness of three RDTs in detecting P. knowlesi from fresh and frozen patient blood samples was evaluated.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext First case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia

Tanizaki R, Ujiie M, Kato Y, Iwagami M, Hashimoto A, Kutsuna S, et al.

Malar J, 2013;12:128.
PMID: 23587117 DOI: 10.1186/1475-2875-12-128

This is the first case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia. In September 2012, a previously healthy 35-year-old Japanese man presented to National Center for Global Health and Medicine in Tokyo with a two-day history of daily fever, mild headaches and mild arthralgia. Malaria parasites were found in the Giemsa-stained thin blood smear, which showed band forms similar to Plasmodium malariae. Although a nested PCR showed the amplification of the primer of Plasmodium vivax and Plasmodium knowlesi, he was finally diagnosed with P. knowlesi mono-infection by DNA sequencing. He was treated with mefloquine, and recovered without any complications. DNA sequencing of the PCR products is indispensable to confirm P. knowlesi infection, however there is limited access to DNA sequencing procedures in endemic areas. The extent of P. knowlesi transmission in Asia has not been clearly defined. There is limited availability of diagnostic tests and routine surveillance system for reporting an accurate diagnosis in the Asian endemic regions. Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext Specific, sensitive and rapid detection of human plasmodium knowlesi infection by loop-mediated isothermal amplification (LAMP) in blood samples

Lau YL, Fong MY, Mahmud R, Chang PY, Palaeya V, Cheong FW, et al.

Malar J, 2011;10:197.
PMID: 21774805 DOI: 10.1186/1475-2875-10-197

The emergence of Plasmodium knowlesi in humans, which is in many cases misdiagnosed by microscopy as Plasmodium malariae due to the morphological similarity has contributed to the needs of detection and differentiation of malaria parasites. At present, nested PCR targeted on Plasmodium ssrRNA genes has been described as the most sensitive and specific method for Plasmodium detection. However, this method is costly and requires trained personnel for its implementation. Loop-mediated isothermal amplification (LAMP), a novel nucleic acid amplification method was developed for the clinical detection of P. knowlesi. The sensitivity and specificity of LAMP was evaluated in comparison to the results obtained via microscopic examination and nested PCR.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext The emerging of the fifth malaria parasite (Plasmodium knowlesi): a public health concern?

Sabbatani S, Fiorino S, Manfredi R

Braz J Infect Dis, 2010 May-Jun;14(3):299-309.
PMID: 20835518

After examining the most recent scientific evidences, which assessed the role of some malaria plasmodia that have monkeys as natural reservoirs, the authors focus their attention on Plasmodium knowlesi. The infective foci attributable to this last Plasmodium species have been identified during the last decade in Malaysia, in particular in the states of Sarawak and Sabah (Malaysian Borneo), and in the Pahang region (peninsular Malaysia). The significant relevance of molecular biology assays (polymerase chain reaction, or PCR, performed with specific primers for P. knowlesi), is underlined, since the traditional microscopic examination does not offer distinguishing features, especially when the differential diagnosis with Plasmodium malariae is of concern. Furthermore, Plasmodium knowlesi disease may be responsible of fatal cases, since its clinical presentation and course is more severe compared with those caused by P. malariae, paralleling a more elevated parasitemia. The most effective mosquito vector is represented by Anopheles latens; this mosquito is a parasite of both humans and monkeys. Among primates, the natural hosts are Macaca fascicularis, M. nemestina, M. inus, and Saimiri scirea. When remarking the possible severe evolution of P. knowlesi malaria, we underline the importance of an early recognition and a timely management, especially in patients who have their first onset in Western Hospitals, after journeys in Southeast Asian countries, and eventually participated in trekking excursions in the tropical forest. When malaria-like signs and symptoms are present, a timely diagnosis and treatment become crucial. In the light of its emerging epidemiological features, P. knowlesi may be added to the reknown human malaria parasites, whith includes P. vivax, P. ovale, P. malariae, and P. falciparum, as the fifth potential ethiologic agent of human malaria. Over the next few years, it will be mandatory to support an adequate surveillance and epidemiological network. In parallel with epidemiological and health care policy studies, also an accurate appraisal of the clinical features of P. knowlesi-affected patients will be strongly needed, since some preliminary experiences seem to show an increased disease severity, associated with increased parasitemia, in parallel with the progressive increase of inter-human infectious passages of this emerging Plasmodium.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext Epidemiology of Plasmodium knowlesi malaria in north-east Sabah, Malaysia: family clusters and wide age distribution

Barber BE, William T, Dhararaj P, Anderios F, Grigg MJ, Yeo TW, et al.

Malar J, 2012;11:401.
PMID: 23216947 DOI: 10.1186/1475-2875-11-401

The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo, with a particularly high incidence in Kudat, Sabah. Little is known however about the epidemiology in this substantially deforested region.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax Malaria in Sabah, Malaysia

William T, Rahman HA, Jelip J, Ibrahim MY, Menon J, Grigg MJ, et al.

PLoS Negl Trop Dis, 2013;7(1):e2026.
PMID: 23359830 DOI: 10.1371/journal.pntd.0002026

BACKGROUND: The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria species over time.
METHODS: Reporting of microscopy-diagnosed malaria cases in Sabah is mandatory. We reviewed all available Department of Health malaria notification records from 1992-2011. Notifications of P. malariae and P. knowlesi were considered as a single group due to microscopic near-identity.
RESULTS: From 1992-2011 total malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. malariae/P. knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈ 100/year in the late 1990s/early 2000s. However, P. malariae/P. knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. malariae/P. knowlesi monoinfections accounted for 70%, 24% and 1% respectively of malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. malariae/P. knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly.
CONCLUSIONS: A significant recent increase has occurred in P. knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens malaria elimination. Determination of transmission dynamics and risk factors for knowlesi malaria is required to guide measures to control this rising incidence.

Matched MeSH terms: Plasmodium knowlesi/isolation & purification*
Fulltext Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII): Comparison with the Duffy Binding Protein (PkDBPαRII)

Fong MY, Rashdi SA, Yusof R, Lau YL

PLoS One, 2016;11(5):e0155627.
PMID: 27195821 DOI: 10.1371/journal.pone.0155627

BACKGROUND: Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII) and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII) is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative) selection. The present study aimed to determine whether similar phenomena occur in PkγRII.
METHODS: Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00) programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00). Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version 4.6.1.3).
RESULTS: A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd) and nucleotide diversity (π) with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative) selection, geographical clustering of haplotypes, and high inter-population genetic differentiation (FST index). The main differences between PkγRII and PkDBPαRII include length polymorphism and no departure from neutrality (as measured by Tajima's D statistics) in the PkγRII.
CONCLUSION: Despite the biological difference between PkγRII and PkDBPαRII, both generally have similar genetic diversity level, natural selection, geographical haplotype clustering and inter-population genetic differentiation index.

Matched MeSH terms: Plasmodium knowlesi/genetics*
Fulltext Crystal structure of Plasmodium knowlesi apical membrane antigen 1 and its complex with an invasion-inhibitory monoclonal antibody

Vulliez-Le Normand B, Faber BW, Saul FA, van der Eijk M, Thomas AW, Singh B, et al.

PLoS One, 2015;10(4):e0123567.
PMID: 25886591 DOI: 10.1371/journal.pone.0123567

The malaria parasite Plasmodium knowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host's humoral response to AMA1.

Matched MeSH terms: Plasmodium knowlesi/immunology*

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