Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations

Human infections with Plasmodium knowlesi, a simian malaria parasite, have been on a steady rise in Sarawak. In 2014 and 2015, 87.3% of the 2,458 malaria cases in Sarawak were diagnosed as knowlesi malaria. This worrying trend calls for an urgent evaluation of the disease progression of P. knowlesi....

Full description

Saved in:
Bibliographic Details
Main Author: TING HUEY, HU
Format: Thesis
Language:English
Published: 2021
Subjects:
Online Access:http://ir.unimas.my/id/eprint/36558/1/Ting%20Huey.pdf
Tags: Add Tag
No Tags, Be the first to tag this record!
id my-unimas-ir.36558
record_format uketd_dc
institution Universiti Malaysia Sarawak
collection UNIMAS Institutional Repository
language English
topic RA0421 Public health
Hygiene
Preventive Medicine
spellingShingle RA0421 Public health
Hygiene
Preventive Medicine
TING HUEY, HU
Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
description Human infections with Plasmodium knowlesi, a simian malaria parasite, have been on a steady rise in Sarawak. In 2014 and 2015, 87.3% of the 2,458 malaria cases in Sarawak were diagnosed as knowlesi malaria. This worrying trend calls for an urgent evaluation of the disease progression of P. knowlesi. Since a prospective study was carried out from 2006-2008 in Kapit, Sarawak, there have been no follow-up studies done on the clinical and laboratory features of knowlesi malaria cases. This paucity of data prevents detailed analysis on the progression and pathology of knowlesi malaria. Hence we conducted a prospective study from 2016-2018 to monitor any changes in clinical and laboratory features of knowlesi malaria by comparing current data with that collected a decade ago with the intention of increasing our knowledge on the pathology of knowlesi malaria. Recently, genome-wide analysis and genotyping of P. knowlesi micro-satellites identified two sub-populations of P. knowlesi in Sarawak and Sabah. Cluster 1 was found mainly associated with long-tailed macaques and Cluster 2 with pig-tailed macaques. We examined whether the two sub-populations contributed to different clinical manifestations and also whether there were any changes in the proportion of the sub-populations over time. Additionally, the current method of genotyping each of the sub-populations involve a single round PCR assay and the development of a hemi-nested PCR assay may prove to be more sensitive. Hemi-nested PCR assays were therefore developed for each sub-population and the Cluster 1 assay was found to be more sensitive and specific but not so for the Cluster 2 assay. Our findings on 420 knowlesi malaria patients at Kapit Hospital showed that there were statistically significant differences between some of the clinical and laboratory parameters of the two sub-populations in both patient groups (Cluster 1 infections had higher proportion of myalgia and abdominal pain; also lower platelet counts, total protein and sodium concentrations, with higher bilirubin and urea concentrations) but the laboratory parameters did not appear to give phenotypic clinical significance. Additionally, Cluster 1 severe cases had significantly lower parasitaemia compared to Cluster 2 severe cases which we postulated to result from parasite-driven factor either through virulence or induction of host response to pathogen. Our findings also showed that Cluster 1 was associated with both peri-domestic (forest fringe) and jungle (interior forest) activities, while Cluster 2 was dominantly associated with jungle exposure. Exposure to these two environments were both age and gender specific, with less women entering the jungle and therefore less likely to acquire Cluster 2 infections. We did not find any significant difference in proportion of the sub-populations between the two patient groups which meant stable ratio between the two sub-populations. Additionally, the temporal change identified in clinical parameters of P. knowlesi such as lower duration of illness, was postulated to be associated with a change in the anti-malarial treatment provided at Kapit Hospital and improved health care accessibility. Based on these results, the increasing number of knowlesi malaria cases over the two time periods was likely to be multifactorial and a result of changes in the environment, macaques or vectors, or from a combination of all three rather than changes in parasite factors. However, the lack of clinical evidence regarding parasite adaptation in our study is not conclusive as we may not have captured the window of change which can stretch to 30 years based on field observation of drug resistance. It will be imperative to undertake future investigation involving in vitro studies such as any difference in life-cycles and preference of red blood cell types to identify the mechanism of pathologies between the two sub-populations as well as vector and macaque hosts’ studies to get a better understanding of this zoonosis.
format Thesis
qualification_name Doctor of Philosophy (PhD.)
qualification_level Doctorate
author TING HUEY, HU
author_facet TING HUEY, HU
author_sort TING HUEY, HU
title Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
title_short Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
title_full Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
title_fullStr Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
title_full_unstemmed Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations
title_sort plasmodium knowlesi sub-populations: genotyping, temporal variations and clinical manifestations
granting_institution Universiti Malaysia Sarawak
granting_department Faculty of Medicine and Health Sciences
publishDate 2021
url http://ir.unimas.my/id/eprint/36558/1/Ting%20Huey.pdf
_version_ 1783728473772130304
spelling my-unimas-ir.365582023-08-17T06:25:01Z Plasmodium knowlesi Sub-populations: Genotyping, Temporal Variations and Clinical Manifestations 2021-08-12 TING HUEY, HU RA0421 Public health. Hygiene. Preventive Medicine Human infections with Plasmodium knowlesi, a simian malaria parasite, have been on a steady rise in Sarawak. In 2014 and 2015, 87.3% of the 2,458 malaria cases in Sarawak were diagnosed as knowlesi malaria. This worrying trend calls for an urgent evaluation of the disease progression of P. knowlesi. Since a prospective study was carried out from 2006-2008 in Kapit, Sarawak, there have been no follow-up studies done on the clinical and laboratory features of knowlesi malaria cases. This paucity of data prevents detailed analysis on the progression and pathology of knowlesi malaria. Hence we conducted a prospective study from 2016-2018 to monitor any changes in clinical and laboratory features of knowlesi malaria by comparing current data with that collected a decade ago with the intention of increasing our knowledge on the pathology of knowlesi malaria. Recently, genome-wide analysis and genotyping of P. knowlesi micro-satellites identified two sub-populations of P. knowlesi in Sarawak and Sabah. Cluster 1 was found mainly associated with long-tailed macaques and Cluster 2 with pig-tailed macaques. We examined whether the two sub-populations contributed to different clinical manifestations and also whether there were any changes in the proportion of the sub-populations over time. Additionally, the current method of genotyping each of the sub-populations involve a single round PCR assay and the development of a hemi-nested PCR assay may prove to be more sensitive. Hemi-nested PCR assays were therefore developed for each sub-population and the Cluster 1 assay was found to be more sensitive and specific but not so for the Cluster 2 assay. Our findings on 420 knowlesi malaria patients at Kapit Hospital showed that there were statistically significant differences between some of the clinical and laboratory parameters of the two sub-populations in both patient groups (Cluster 1 infections had higher proportion of myalgia and abdominal pain; also lower platelet counts, total protein and sodium concentrations, with higher bilirubin and urea concentrations) but the laboratory parameters did not appear to give phenotypic clinical significance. Additionally, Cluster 1 severe cases had significantly lower parasitaemia compared to Cluster 2 severe cases which we postulated to result from parasite-driven factor either through virulence or induction of host response to pathogen. Our findings also showed that Cluster 1 was associated with both peri-domestic (forest fringe) and jungle (interior forest) activities, while Cluster 2 was dominantly associated with jungle exposure. Exposure to these two environments were both age and gender specific, with less women entering the jungle and therefore less likely to acquire Cluster 2 infections. We did not find any significant difference in proportion of the sub-populations between the two patient groups which meant stable ratio between the two sub-populations. Additionally, the temporal change identified in clinical parameters of P. knowlesi such as lower duration of illness, was postulated to be associated with a change in the anti-malarial treatment provided at Kapit Hospital and improved health care accessibility. Based on these results, the increasing number of knowlesi malaria cases over the two time periods was likely to be multifactorial and a result of changes in the environment, macaques or vectors, or from a combination of all three rather than changes in parasite factors. However, the lack of clinical evidence regarding parasite adaptation in our study is not conclusive as we may not have captured the window of change which can stretch to 30 years based on field observation of drug resistance. It will be imperative to undertake future investigation involving in vitro studies such as any difference in life-cycles and preference of red blood cell types to identify the mechanism of pathologies between the two sub-populations as well as vector and macaque hosts’ studies to get a better understanding of this zoonosis. Universiti Malaysia Sarawak (UNIMAS) 2021-08 Thesis http://ir.unimas.my/id/eprint/36558/ http://ir.unimas.my/id/eprint/36558/1/Ting%20Huey.pdf text en validuser phd doctoral Universiti Malaysia Sarawak Faculty of Medicine and Health Sciences Tunku Abdul Rahman Sarawak Scholarship Foundation Universiti Malaysia Sarawak Dana Pelajar PhD Universiti Malaysia Sarawak Top Down grant Sarawak State Government REFERENCES Aguilera, F., Orlandi, F., Ruiz-Valenzuela, L., Msallem, M., & Fornaciari, M. (2015). Analysis and interpretation of long temporal trends in cumulative temperatures and olive reproductive features using a seasonal trend decomposition procedure. Agricultural and Forest Meteorology, 203, 208–216. https://doi.org/10.1016/j.agrformet.2014.11.019 Ahmed, M. A., Fauzi, M., & Han, E.-T. (2018). Genetic diversity and natural selection of Plasmodium knowlesi merozoite surface protein 1 paralog gene in Malaysia. Malaria Journal, 17(1), 115. https://doi.org/10.1186/s12936-018-2256-y Ahmed, M. A., Fong, M. Y., Lau, Y. L., & Yusof, R. (2016). Clustering and genetic differentiation of the normocyte binding protein (nbpxa) of Plasmodium knowlesi clinical isolates from Peninsular Malaysia and Malaysia Borneo. Malaria Journal, 15(1), 241. https://doi.org/10.1186/s12936-016-1294-6 Ahmed, M. A., Lau, Y. L., & Quan, F.-S. (2018). Diversity and natural selection on the thrombospondin-related adhesive protein (TRAP) gene of Plasmodium knowlesi in Malaysia. Malaria Journal, 17(1), 274. https://doi.org/10.1186/s12936-018-2423-1 Ahmed, M. A., Pinheiro, M. M., Divis, P. C., Siner, A., Zainudin, R., Wong, I. T., Lu, C. W., Singh-Khaira, S. K., Millar, S. B., Lynch, S., Willmann, M., Singh, B., Krishna, S., & Cox-Singh, J. (2014). Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members. PLoS Neglected Tropical Diseases, 8(8), e3086. https://doi.org/10.1371/journal.pntd.0003086 Amir, A., Cheong, F. W., de Silva, J. R., Liew, J. W. K., & Lau, Y. L. (2018). Plasmodium knowlesi malaria: current research perspectives. Infection and Drug Resistance, 11, 1145–1155. https://doi.org/10.2147/IDR.S148664 Antinori, S., Galimberti, L., Milazzo, L., & Corbellino, M. (2012). Biology of human malaria plasmodia including Plasmodium knowlesi. Mediterranean Journal of Hematology and Infectious Diseases, 4(1), e2012013. https://doi.org/10.4084/mjhid.2012.013 Assefa, S., Lim, C., Preston, M. D., Duffy, C. W., Nair, M. B., Adroub, S. A., Kadir, K. A., Goldberg, J. M., Neafsey, D. E., Divis, P., Clark, T. G., Duraisingh, M. T., Conway, D. J., Pain, A., & Singh, B. (2015). Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi. Proceedings of the National Academy of Sciences, 112(42), 13027–13032. https://doi.org/10.1073/pnas.1509534112 Austin, S. C., Stolley, P. D., & Lasky, T. (1992). The history of malariotherapy for neurosyphilis: modern parallels. JAMA: The Journal of the American Medical Association, 268(4), 516–519. https://doi.org/10.1001/jama.1992.03490040092031 Barber, B. E., Grigg, M. J., Piera, K. A., William, T., Cooper, D. J., Plewes, K., Dondorp, A. M., Yeo, T. W., & Anstey, N. M. (2018). Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury. Emerging Microbes & Infections, 7(1), 1–10. https://doi.org/10.1038/s41426-018-0105-2 Barber, B. E., Grigg, M. J., William, T., Yeo, T. W., & Anstey, N. M. (2017). The treatment of Plasmodium knowlesi malaria. Trends in Parasitology, 33(3), 242–253. https://doi.org/10.1016/j.pt.2016.09.002 Barber, B. E., Russell, B., Grigg, M. J., Zhang, R., William, T., Amir, A., Lau, Y. L., Chatfield, M. D., Dondorp, A. M., Anstey, N. M., & Yeo, T. W. (2018). Reduced red blood cell deformability in Plasmodium knowlesi malaria. Blood Advances, 2(4), 433–443. https://doi.org/10.1182/bloodadvances.2017013730 Barber, B. E., William, T., Grigg, M. J., Menon, J., Auburn, S., Marfurt, J., Anstey, N. M., & Yeo, T. W. (2013). A prospective comparative study of knowlesi, falciparum, and vivax malaria in sabah, Malaysia: High proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy. Clinical Infectious Diseases, 56(3), 383–397. https://doi.org/10.1093/cid/cis902 Berry, A., Iriart, X., Wilhelm, N., Valentin, A., Cassaing, S., Witkowski, B., Benoit-Vical, F., Menard, S., Olagnier, D., Fillaux, J., Sire, S., Le Coustumier, A., & Magnaval, J. F. (2011). Case report: Imported Plasmodium knowlesi malaria in a french tourist returning from Thailand. American Journal of Tropical Medicine and Hygiene, 84(4), 535–538. https://doi.org/10.4269/ajtmh.2011.10-0622 Brasil, P., Zalis, M. G., de Pina-Costa, A., Siqueira, A. M., Júnior, C. B., Silva, S., Areas, A. L. L., Pelajo-Machado, M., de Alvarenga, D. A. M., da Silva Santelli, A. C. F., Albuquerque, H. G., Cravo, P., Santos de Abreu, F. V., Peterka, C. L., Zanini, G. M., Suárez Mutis, M. C., Pissinatti, A., Lourenço-de-Oliveira, R., de Brito, C. F. A., … Daniel-Ribeiro, C. T. (2017). Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation. The Lancet Global Health, 5(10), e1038–e1046. https://doi.org/10.1016/S2214-109X(17)30333-9 Bray, R. S., & Garnham, P. C. C. (1982). The life-cycle of primate malaria parasites. British Medical Bulletin, 38(2), 117–122. https://doi.org/10.1093/oxfordjournals.bmb.a071746 Bronner, U., Divis, P. C. S., Färnert, A., & Singh, B. (2009). Swedish traveller with Plasmodium knowlesi malaria after visiting Malaysian Borneo. Malaria Journal, 8(1), 1–5. https://doi.org/10.1186/1475-2875-8-15 Bruce-Chwatt, L. J. (1968). Malaria zoonosis in relation to malaria eradication. Tropical and Geographical Medicine, 20(1), 50–87. http://www.ncbi.nlm.nih.gov/pubmed/4966749 Busher, J. T. (1990). Serum Albumin and Globulin. In H. K. Walker, W. D. Hall, & J. W. Hurst (Eds.), Clinical Methods: The History, Physical, and Laboratory Examinations (3rd ed., pp. 497–499). Butterworths. http://www.ncbi.nlm.nih.gov/pubmed/21250048 Butcher, G. A., & Mitchell, G. H. (2018). The role of Plasmodium knowlesi in the history of malaria research. Parasitology, 145(1), 6–17. https://doi.org/10.1017/S0031182016001888 Candido Moura, G., Barcelos, D., Epiphanio, S., & Santos Ortolan, L. dos. (2017). Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome. Journal of Ancient Diseases & Preventive Remedies, 5(4), e1000171. https://doi.org/10.4172/2329-8731.1000171 Carme, B., & Demar, M. (2013). Hyperparasitaemia during bouts of malaria in French Guiana. Malaria Journal, 12(20). https://doi.org/10.1186/1475-2875-12-20 Carter, R., & Mendis, K. N. (2002). Evolutionary and historical aspects of the burden of malaria. Clinical Microbiology Reviews, 15(4), 564–594. https://doi.org/10.1128/CMR.15.4.564-594.2002 Chin, W., Contacos, P. G., Coatney, G. R., & Kimball, H. R. (1965). A naturally acquired quotidian-type malaria in man. Science, 149, 865. Chin, W., Contacos, P. G., Collins, W. E., Jeter, M. H., & Alpert, E. (1968). Experimental mosquito-transmission of Plasmodium knowlesi to man and monkey. The American Journal of Tropical Medicine and Hygiene, 17(3), 355–358. https://doi.org/10.4269/ajtmh.1968.17.355 Chuang, J. Y., & Hii, K. C. (2019). The deceit of Plasmodium knowlesi : report of four malaria knowlesi death in Kapit divisional hospital. In 11th Sarawak State Research Day 2019. Cleveland, R. B., Cleveland, W. S., McRae, J. E., & Terpenning, I. (1990). STL: A seasonal-trend decomposition procedure based on loess. Journal of Official Statistics, 6(1), 3–73. https://doi.org/doi.org/citeulike-article-id:1435502 Coatney, G. R., Chin, W., Contacos, P. G., & King, H. K. (1966). Plasmodium inui, a quartan-type old world monkeys transmissible to man. The Journal of Parasitology, 52(4), 660–663. Coatney, G. R., Collins, W. E., Warren, M., & Contacos, P. G. (2003). The Primate Malarias [original book published 1971] (Version 1). CD-ROM. CDC. Collins, W. E. (2012). Plasmodium knowlesi : A malaria parasite of monkeys and humans. Annual Review of Entomology, 57(1), 107–121. https://doi.org/10.1146/annurev-ento-121510-133540 Collins, W. E., Contacos, P. G., & Guinn, E. G. (1967). Studies on the transmission of simian malarias II. Transmission of the H strain of Plasmodium knowlesi by Anopheles balabacensis balabacensis. The Journal of Parasitology, 53(4), 841–844. https://doi.org/10.2307/3276783 Contacos, P. G., Elder, H. A., Coatney, G. R., & Genther, C. (1962). Man to man transfer of two strains of Plasmodium cynomolgi by mosquito bite. The American Journal of Tropical Medicine and Hygiene, 11(2), 186–193. https://doi.org/10.4269/ajtmh.1962.11.186 Contacos, P. G., Lunn, J. S., Coatney, G. R., Kilpatrick, J. W., & Jones, F. E. (1963). Quartan-type malaria parasite of new world monkeys transmissible to man. Science, 142(3593), 676. https://doi.org/10.1126/science.142.3593.676 Conway, D. J. (2007). Molecular epidemiology of malaria. Clinical Microbiology Reviews, 20(1), 188–204. https://doi.org/10.1128/CMR.00021-06 Cooper, D. J., Rajahram, G. S., William, T., Jelip, J., Mohammad, R., Benedict, J., Alaza, D. A., Malacova, E., Yeo, T. W., Grigg, M. J., Anstey, N. M., & Barber, B. E. (2019). Plasmodium knowlesi Malaria in Sabah, Malaysia, 2015–2017: Ongoing Increase in Incidence Despite Near-elimination of the Human-only Plasmodium Species. Clinical Infectious Diseases, 70(3), 361–367. https://doi.org/10.1093/cid/ciz237 Cordina, C. J., Culleton, R., Jones, B. L., Smith, C. C., MacConnachie, A. A., Coyne, M. J., & Alexander, C. L. (2014). Plasmodium knowlesi: Clinical presentation and laboratory diagnosis of the first human case in a Scottish traveler. Journal of Travel Medicine, 21(5), 357–360. https://doi.org/10.1111/jtm.12131 Cox-Singh, J. (2009). Knowlesi malaria in Vietnam. Malaria Journal, 8(1), 1–2. https://doi.org/10.1186/1475-2875-8-269 Cox-Singh, J., Hiu, J., Lucas, S. B., Divis, P. C., Zulkarnaen, M., Chandran, P., Wong, K. T., Adem, P., Zaki, S. R., Singh, B., & Krishna, S. (2010). Severe malaria - A case of fatal Plasmodium knowlesi infection with post-mortem findings: A case report. Malaria Journal, 9(1), 1–7. https://doi.org/10.1186/1475-2875-9-10 Cox-Singh, J., Mahayet, S., Abdullah, M. S., & Singh, B. (1997). Increased sensitivity of malaria detection by nested polymerase chain reaction using simple sampling and DNA extraction. International Journal for Parasitology, 27(12), 1575–1577. https://doi.org/10.1016/S0020-7519(97)00147-1 Cox, F. E. (2010). History of the discovery of the malaria parasites and their vectors. Parasites & Vectors, 3(1), 5. https://doi.org/10.1186/1756-3305-3-5 Daneshvar, C. (2013). Clinical studies on naturally acquired Plasmodium knowlesi infections in humans (Phd Thesis). University of London, St George’s. Daneshvar, C., Davis, T. M., Cox-Singh, J., Rafa’ee, M. Z., Zakaria, S. K., Divis, P. C., & Singh, B. (2010). Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections. Malaria Journal, 9(1), 238. https://doi.org/10.1186/1475-2875-9-238 Daneshvar, C., Davis, T. M. E., Cox‐Singh, J., Rafa’ee, M. Z., Zakaria, S. K., Divis, P. C. S., & Singh, B. (2009). Clinical and laboratory features of human Plasmodium knowlesi infection. Clinical Infectious Diseases, 49(6), 852–860. https://doi.org/10.1086/605439 Daneshvar, C., William, T., & Davis, T. M. E. (2018). Clinical features and management of Plasmodium knowlesi infections in humans. Parasitology, 145(1), 18–31. https://doi.org/10.1017/S0031182016002638 Das, S. (2011). A study of coagulation profile in falciparum malaria. Orissa Physicians Journal, 7, 13–17. Davidson, G., Chua, T. H., Cook, A., Speldewinde, P., & Weinstein, P. (2019a). Defining the ecological and evolutionary drivers of Plasmodium knowlesi transmission within a multi-scale framework. Malaria Journal, 18(1), 1–13. https://doi.org/10.1186/s12936-019-2693-2 Davidson, G., Chua, T. H., Cook, A., Speldewinde, P., & Weinstein, P. (2019b). The Role of Ecological Linkage Mechanisms in Plasmodium knowlesi Transmission and Spread. EcoHealth, 16(4), 594–610. https://doi.org/10.1007/s10393-019-01395-6 Deane, L. M., Deane, M. P., & Ferreira Neto, J. (1966). Studies on transmission of simian malaria and on a natural infection of man with Plasmodium simium in Brazil. Bulletin of the World Health Organization, 35(5), 805–808. http://www.ncbi.nlm.nih.gov/pubmed/5297817 Deroost, K., Pham, T.-T., Opdenakker, G., & Van den Steen, P. E. (2016). The immunological balance between host and parasite in malaria. FEMS Microbiology Reviews, 40(2), 208–257. https://doi.org/10.1093/femsre/fuv046 Desloire, S., Valiente Moro, C., Chauve, C., & Zenner, L. (2006). Comparison of four methods of extracting DNA from D. gallinae (Acari: Dermanyssidae). Veterinary Research, 37(5), 725–732. https://doi.org/10.1051/vetres:2006031 Diez Benavente, E., Florez de Sessions, P., Moon, R. W., Holder, A. A., Blackman, M. J., Roper, C., Drakeley, C. J., Pain, A., Sutherland, C. J., Hibberd, M. L., Campino, S., & Clark, T. G. (2017). Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations. PLOS Genetics, 13(9), e1007008. https://doi.org/10.1371/journal.pgen.1007008 Divis, P. C. S. (2007). Identification and molecular characterisation of malaria parasites of macaques in Kapit, Sarawak (MSc Thesis). Universiti Malaysia Sarawak. Divis, P. C. S. (2017). Population genetic structure and genomic divergence in Plasmodium knowlesi (PhD Thesis). London School of Hygiene and Tropical Medicine. Divis, P. C. S., Duffy, C. W., Kadir, K. A., Singh, B., & Conway, D. J. (2018). Genome-wide mosaicism in divergence between zoonotic malaria parasite subpopulations with separate sympatric transmission cycles. Molecular Ecology, 27(4), 860–870. https://doi.org/10.1111/mec.14477 Divis, P. C. S., Hu, T. H., Kadir, K. A., Mohammad, D. S. A., Hii, K. C., Daneshvar, C., Conway, D. J., & Singh, B. (2020). Efficient surveillance of Plasmodium knowlesi genetic subpopulations, Malaysian Borneo, 2000–2018. Emerging Infectious Diseases, 26(7), 1392–1398. https://doi.org/10.3201/eid2607.190924 Divis, P. C. S., Lin, L. C., Rovie-Ryan, J. J., Kadir, K. A., Anderios, F., Hisam, S., Sharma, R. S. K., Singh, B., & Conway, D. J. (2017). Three divergent subpopulations of the malaria parasite Plasmodium knowlesi. Emerging Infectious Diseases, 23(4), 616–624. Divis, P. C. S., Singh, B., Anderios, F., Hisam, S., Matusop, A., Kocken, C. H., Assefa, S. A., Duffy, C. W., & Conway, D. J. (2015). Admixture in humans of two divergent Plasmodium knowlesi populations associated with different macaque host species. PLoS Pathogens, 11(5), 1–17. https://doi.org/10.1371/journal.ppat.1004888 Dondorp, A. M., Lee, S. J., Faiz, M. A., Mishra, S., Price, R., Tjitra, E., Than, M., Htut, Y., Mohanty, S., Yunus, E. Bin, Rahman, R., Nosten, F., Anstey, N. M., Day, N. P. J., & White, N. J. (2008). The relationship between age and the manifestations of and mortality associated with severe malaria. Clinical Infectious Diseases, 47(2), 151–157. https://doi.org/10.1086/589287 Doolan, D. L., Dobaño, C., & Baird, J. K. (2009). Acquired immunity to malaria. Clinical Microbiology Reviews, 22(1), 13–36. https://doi.org/10.1128/CMR.00025-08 Duval, L., & Ariey, F. (2012). Ape Plasmodium parasites as a source of human outbreaks. Clinical Microbiology and Infection, 18(6), 528–532. https://doi.org/10.1111/j.1469-0691.2012.03825.x Ehrhardt, J., Trein, A., Kremsner, P., & Frank, M. (2013). Plasmodium knowlesi and HIV co-infection in a German traveller to Thailand. Malaria Journal, 12(1), 283–288. https://doi.org/10.1186/1475-2875-12-283 Eyles, D. E. (1963). The species of simian malaria: Taxonomy, morphology, life cycle, and geographical distribution of the monkey species. The Journal of Parasitology, 49(6), 866–887. https://doi.org/10.2307/3275712 Eyles, D. E., Coatney, G. R., & Getz, M. E. (1960). Vivax-Type Malaria Parasite of Macaques Transmissible to Man. Science, 131(3416), 1812–1813. https://doi.org/10.1126/science.131.3416.1812 Eyles, D. E., Laing, A. B. G., & Dobrovolny, C. G. (1962). The malaria parasites of the pig-tailed macaque, Macaca nemestrina nemestrina (linnaeus), in Malaya. Indian Journal of Malariology, 16(3), 285–298. https://www.cabdirect.org/cabdirect/abstract/19632901595 Eyles, D. E., Laing, A. B. G., Warren, M., Sandosham, A. A., & Wharton, R. H. (1962). Malaria parasites of the Malayan leaf monkeys of the genus Presbytis. Medical Journal of Malaya, 17, 85–86. Fatih, F. A., Siner, A., Ahmed, A., Woon, L. C., Craig, A. G., Singh, B., Krishna, S., & Cox-Singh, J. (2012). Cytoadherence and virulence - The case of Plasmodium knowlesi malaria. Malaria Journal, 11, 1–6. https://doi.org/10.1186/1475-2875-11-33 Faust, C., & Dobson, A. P. (2015). Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium. One Health, 1, 66–75. https://doi.org/10.1016/j.onehlt.2015.10.001 Figtree, M., Lee, R., Bain, L., Kennedy, T., Mackertich, S., Urban, M., Cheng, Q., & Hudson, B. J. (2010). Plasmodium knowlesi in human, Indonesian Borneo. Emerging Infectious Diseases, 16(4), 672–674. https://doi.org/10.3201/eid1604.091624 Fong, Y. L., Cadigan, F. C., & Coatney, G. R. (1971). A presumptive case of naturally occuring Plasmodium knowlesi malaria in man in Malaysia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 65, 839–840. Fooden, J. (1994). Malaria in macaques. International Journal of Primatology, 15(4), 573–596. https://doi.org/10.1007/BF02735972 Fornace, K. M., Brock, P. M., Abidin, T. R., Grignard, L., Herman, L. S., Chua, T. H., Daim, S., William, T., Patterson, C. L. E. B., Hall, T., Grigg, M. J., Anstey, N. M., Tetteh, K. K. A., Cox, J., & Drakeley, C. J. (2019). Environmental risk factors and exposure to the zoonotic malaria parasite Plasmodium knowlesi across northern Sabah, Malaysia: a population-based cross-sectional survey. The Lancet Planetary Health, 3(4), e179–e186. https://doi.org/10.1016/S2542-5196(19)30045-2 Galinski, M. R., & Barnwell, J. W. (2009). Monkey malaria kills four humans. Trends in Parasitology, 25(5), 200–204. https://doi.org/10.1016/j.pt.2009.02.002 Garnham, P. C. C. (1966). Malaria parasites and other Haemosporidia. Blackwell Scientific. Gautret, P., & Motard, A. (1999). Periodic infectivity of Plasmodium gametocytes to the vector. A review. Parasite, 6(2), 103–111. https://doi.org/10.1051/parasite/1999062103 Goman, M., Mons, B., & Scaife, J. (1991). The complete sequence of a Plasmodium malariae SSUrRNA gene and its comparison to other plasmodial SSUrRNA genes. Molecular and Biochemical Parasitology, 45(2), 281–288. https://doi.org/10.1016/0166-6851(91)90096-o Goodhead, I., Capewell, P., Bailey, J. W., Beament, T., Chance, M., Kay, S., Forrester, S., MacLeod, A., Taylor, M., Noyes, H., & Hall, N. (2013). Whole-genome sequencing of Trypanosoma brucei reveals introgression between subspecies that is associated with virulence. MBio, 4(4), 1–8. https://doi.org/10.1128/mBio.00197-13 Govindasamy, G., Barber, B. E., Ghani, S. A., William, T., Grigg, M. J., Borooah, S., Dhillon, B., Dondorp, A. M., Yeo, T. W., Anstey, N. M., & Maude, R. J. (2016). Retinal changes in uncomplicated and severe Plasmodium knowlesi malaria. Journal of Infectious Diseases, 213(9), 1476–1482. https://doi.org/10.1093/infdis/jiv746 Grigg, M. J., Cox, J., William, T., Jelip, J., Fornace, K. M., Brock, P. M., von Seidlein, L., Barber, B. E., Anstey, N. M., Yeo, T. W., & Drakeley, C. J. (2017). Individual-level factors associated with the risk of acquiring human Plasmodium knowlesi malaria in Malaysia: a case-control study. The Lancet Planetary Health, 1(3), e97–e104. https://doi.org/10.1016/S2542-5196(17)30031-1 Grigg, M. J., William, T., Barber, B. E., Rajahram, G. S., Menon, J., Schimann, E., Piera, K., Wilkes, C. S., Patel, K., Chandna, A., Drakeley, C. J., Yeo, T. W., & Anstey, N. M. (2018). Age-related clinical spectrum of Plasmodium knowlesi malaria and predictors of severity. Clinical Infectious Diseases, 67(3), 350–359. https://doi.org/10.1093/cid/ciy065 Gunalan, K., Gao, X., Yap, S. S. L., Huang, X., & Preiser, P. R. (2013). The role of the reticulocyte-binding-like protein homologues of Plasmodium in erythrocyte sensing and invasion. Cellular Microbiology, 15(1), 35–44. https://doi.org/10.1111/cmi.12038 Hanson, J., Phu, N. H., Hasan, M. U., Charunwatthana, P., Plewes, K., Maude, R. J., Prapansilp, P., Kingston, H. W. F., Mishra, S. K., Mohanty, S., Price, R. N., Faiz, M. A., Dondorp, A. M., White, N. J., Hien, T. T., & Day, N. P. J. (2015). The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis. BMC Medicine, 13(97). https://doi.org/10.1186/s12916-015-0324-5 Hayakawa, T., Culleton, R., Otani, H., Horii, T., & Tanabe, K. (2008). Big bang in the evolution of extant malaria parasites. Molecular Biology and Evolution, 25(10), 2233–2239. https://doi.org/10.1093/molbev/msn171 Herdiana, H., Cotter, C., Coutrier, F. N., Zarlinda, I., Zelman, B. W., Tirta, Y. K., Greenhouse, B., Gosling, R. D., Baker, P., Whittaker, M., & Hsiang, M. S. (2016). Malaria risk factor assessment using active and passive surveillance data from Aceh Besar, Indonesia, a low endemic, malaria elimination setting with Plasmodium knowlesi, Plasmodium vivax, and Plasmodium falciparum. Malaria Journal, 15(1), 1–15. https://doi.org/10.1186/s12936-016-1523-z Hoffman, S. L., Campbell, C. C. (Kent), & White, N. J. (2011). Malaria. In R. L. Guerrant, D. H. Walker, & P. F. Weller (Eds.), Tropical Infectious Diseases: Principles, Pathogens and Practice (3rd ed., pp. 646–675). Elsevier. https://doi.org/10.1016/B978-0-7020-3935-5.00096-3 Hsu, L. Y. (2015). Malaria, P. knowlesi - Singapore: ex Brunei (Ulu Temburong Nat’l Park). https://promedmail.org/;Archive Number: 20151204.3839386 Hussin, N., Lim, Y. A. L., Goh, P. P., William, T., Jelip, J., & Mudin, R. N. (2020). Updates on malaria incidence and profile in Malaysia from 2013 to 2017. Malaria Journal, 19(1), 1–14. https://doi.org/10.1186/s12936-020-3135-x Imwong, M., Madmanee, W., Suwannasin, K., Kunasol, C., Peto, T. J., Tripura, R., Von Seidlein, L., Nguon, C., Davoeung, C., Day, N. P. J., Dondorp, A. M., & White, N. J. (2019). Asymptomatic natural human infections with the simian malaria parasites Plasmodium cynomolgi and Plasmodium knowlesi. Journal of Infectious Diseases, 219(5), 695–702. https://doi.org/10.1093/infdis/jiy519 Iwanaga, S., Kaneko, I., Kato, T., & Yuda, M. (2012). Identification of an AP2-family Protein That Is Critical for Malaria Liver Stage Development. PLoS ONE, 7(11), e47557. https://doi.org/10.1371/journal.pone.0047557 Jeslyn, W. P. S., Huat, T. C., Vernon, L., Irene, L. M. Z., Sung, L. K., Jarrod, L. P., Singh, B., & Ching, N. L. (2011). Molecular epidemiological investigation of Plasmodium knowlesi in humans and macaques in Singapore. Vector-Borne and Zoonotic Diseases, 11(2), 131–135. https://doi.org/10.1089/vbz.2010.0024 Jiang, N., Chang, Q., Sun, X., Lu, H., Yin, J., Zhang, Z., Wahlgren, M., & Chen, Q. (2010). Differential Prevalence of Plasmodium Infections and Cryptic Plasmodium knowlesi Malaria in Humans in Thailand. Emerging Infectious Diseases, 16(9), 1476–1478. https://doi.org/10.1086/597414 Jongwutiwes, S., Buppan, P., Kosuvin, R., Seethamchai, S., Pattanawong, U., Sirichaisinthop, J., & Putaporntip, C. (2011). Plasmodium knowlesi malaria in humans and macaques, Thailand. Emerging Infectious Diseases, 17(10), 1799–1806. https://doi.org/10.3201/eid1710.110349 Josling, G. A., & Llinás, M. (2015). Sexual development in Plasmodium parasites: Knowing when it’s time to commit. Nature Reviews Microbiology, 13(9), 573–587. https://doi.org/10.1038/nrmicro3519 Khim, N., Siv, S., Kim, S., Mueller, T., Fleischmann, E., Singh, B., Divis, P. C. S., Steenkeste, N., Duval, L., Bouchier, C., Duong, S., Ariey, F., & Ménard, D. (2011). Plasmodium knowlesi infection in humans, Cambodia, 2007-2010. Emerging Infectious Diseases, 17(10), 1900–1902. https://doi.org/10.3201/eid1710.110355 Kho, S., Barber, B. E., Johar, E., Andries, B., Poespoprodjo, J. R., Kenangalem, E., Piera, K. A., Ehmann, A., Price, R. N., William, T., Woodberry, T., Foote, S., Minigo, G., Yeo, T. W., Grigg, M. J., Anstey, N. M., & McMorran, B. J. (2018). Platelets kill circulating parasites of all major Plasmodium species in human malaria. Blood, 132(12), 1332–1344. https://doi.org/10.1182/blood-2018-05-849307 Kilpatrick, A. M., Kramer, L. D., Jones, M. J., Marra, P. P., Daszak, P., & Fonseca, D. M. (2007). Genetic influences on mosquito feeding behavior and the emergence of zoonotic pathogens. American Journal of Tropical Medicine and Hygiene, 77(4), 667–671. Kilpatrick, A. M., & Randolph, S. E. (2012). Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. The Lancet, 380(9857), 1946–1955. https://doi.org/10.1016/S0140-6736(12)61151-9 Kingston, H. W., Ghose, A., Plewes, K., Ishioka, H., Leopold, S. J., Maude, R. J., Paul, S., Intharabut, B., Silamut, K., Woodrow, C., Day, N. P. J., Chotivanich, K., Anstey, N. M., Hossain, A., White, N. J., & Dondorp, A. M. (2017). Disease severity and effective parasite multiplication rate in falciparum malaria. Open Forum Infectious Diseases, 4(4), 1–4. https://doi.org/10.1093/ofid/ofx169 Knowles, R., & Gupta, B. M. Das. (1932). A study of monkey-malaria, and its experimental transmission to man. The Indian Medical Gazette, 67(6), 301–320. https://doi.org/10.4269/ajtmh.1968.17.355 Kuo, M., Chiang, T., & Tsai, W. (2009). A case report of simian malaria, Plasmodium knowlesi , in a Taiwanese traveler from Palawan island , the Philippines. Taiwan Epidemiology Bulletin, 161, 178–191. Lalremruata, A., Magris, M., Vivas-Martínez, S., Koehler, M., Esen, M., Kempaiah, P., Jeyaraj, S., Perkins, D. J., Mordmüller, B., & Metzger, W. G. (2015). Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon. EBioMedicine, 2(9), 1186–1192. https://doi.org/10.1016/j.ebiom.2015.07.033 Laman Web Majlis Daerah Kapit. (n.d.). Retrieved July 23, 2019, from https://kapitdc.sarawak.gov.my/page-0-150-67-Pengenalan-Bahagian-Kapit.html Lambrecht, F. L., Dunn, F. L., & Eyles, D. E. (1961). Isolation of Plasmodium knowlesi from Philippine macaques. Nature, 191(4793), 1117–1118. https://doi.org/10.1038/1911117a0 Last, J. M. (2001). A Dictionary of Epidemiology (4th ed.). Oxford University Press. Lau, Y.-L. (2011). Plasmodium knowlesi reinfection in human. Emerging Infectious Diseases, 17(7), 1314–1315. https://doi.org/10.3201/eid1707.101295 Lee, K.-S., Cox-Singh, J., & Singh, B. (2009). Morphological features and differential counts of Plasmodium knowlesi parasites in naturally acquired human infections. Malaria Journal, 8(1), 73. https://doi.org/10.1186/1475-2875-8-73 Lee, K.-S., Divis, P. C. S., Zakaria, S. K., Matusop, A., Julin, R. A., Conway, D. J., Cox-Singh, J., & Singh, B. (2011). Plasmodium knowlesi: Reservoir hosts and tracking the emergence in humans and macaques. PLoS Pathogens, 7(4), e1002015. https://doi.org/10.1371/journal.ppat.1002015 Lim, C., Hansen, E., Desimone, T. M., Moreno, Y., Junker, K., Bei, A., Brugnara, C., Buckee, C. O., & Duraisingh, M. T. (2013). Expansion of host cellular niche can drive adaptation of a zoonotic malaria parasite to humans. Nature Communications, 4, 1638–1639. https://doi.org/10.1038/ncomms2612 Lin, L. C., & Shah, M. K. (2018). A review of Plasmodium knowlesi among macaques in Malaysia. Advances in Animal and Veterinary Sciences, 6(4), 516–522. https://doi.org/10.17582/journal.aavs/2018/6.4.169.175 Liu, W., Li, Y., Learn, G. H., Rudicell, R. S., Robertson, J. D., Keele, B. F., Ndjango, J.-B. N., Sanz, C. M., Morgan, D. B., Locatelli, S., Gonder, M. K., Kranzusch, P. J., Walsh, P. D., Delaporte, E., Mpoudi-Ngole, E., Georgiev, A. V., Muller, M. N., Shaw, G. M., Peeters, M., … Hahn, B. H. (2010). Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature, 467(7314), 420–425. https://doi.org/10.1038/nature09442 Liu, W., Li, Y., Shaw, K. S., Learn, G. H., Plenderleith, L. J., Malenke, J. A., Sundararaman, S. A., Ramirez, M. A., Crystal, P. A., Smith, A. G., Bibollet-Ruche, F., Ayouba, A., Locatelli, S., Esteban, A., Mouacha, F., Guichet, E., Butel, C., Ahuka-Mundeke, S., Inogwabini, B.-I., … Sharp, P. M. (2014). African origin of the malaria parasite Plasmodium vivax. Nature Communications, 5(3346). https://doi.org/10.1038/ncomms4346 Lorenz, T. C. (2012). Polymerase chain reaction: Basic protocol plus troubleshooting and optimization strategies. Journal of Visualized Experiments, 63, 1–15. https://doi.org/10.3791/3998 Lubis, I. N. D., Wijaya, H., Lubis, M., Lubis, C. P., Divis, P. C. S., Beshir, K. B., & Sutherland, C. J. (2017). Contribution of Plasmodium knowlesi to multispecies human malaria infections in north Sumatera, Indonesia. The Journal of Infectious Diseases, 215(7), 1148–1155. https://doi.org/10.1093/infdis/jix091 Luchavez, J., Espino, F., Curameng, P., Espina, R., Bell, D., Chiodini, P., Nolder, D., Sutherland, C., Lee, K. S., & Singh, B. (2008). Human infections with Plasmodium knowlesi, the Philippines. Emerging Infectious Diseases, 14(5), 811–813. https://doi.org/10.3201/eid1405.071407 Lucky, A. B., Sakaguchi, M., Katakai, Y., Kawai, S., Yahata, K., Templeton, T. J., & Kaneko, O. (2016). Plasmodium knowlesi Skeleton-Binding Protein 1 Localizes to the ‘Sinton and Mulligan’ Stipplings in the Cytoplasm of Monkey and Human Erythrocytes. PLoS ONE, 11(10), e0164272. https://doi.org/10.1371/journal.pone.0164272 Mackinnon, M. J., & Read, A. F. (1999). Genetic relationships between parasite virulence and transmission in the rodent malaria Plasmodium chabaudi. Evolution, 53(3), 689. https://doi.org/10.2307/2640710 Mackinnon, M. J., & Read, A. F. (2004). Virulence in malaria: An evolutionary viewpoint. Philosophical Transactions of the Royal Society B: Biological Sciences, 359(1446), 965–986. https://doi.org/10.1098/rstb.2003.1414 MacNee, W., Rabinovich, R. A., & Choudhury, G. (2014). Ageing and the border between health and disease. European Respiratory Journal, 44(5), 1332–1352. https://doi.org/10.1183/09031936.00134014 Malaguarnera, L., & Musumeci, S. (2002). The immune response to Plasmodium falciparum malaria. Lancet Infectious Diseases, 2(8), 472–478. https://doi.org/10.1016/S1473-3099(02)00344-4 Marchand, R. P., Culleton, R., Maeno, Y., Quang, N. T., & Nakazawa, S. (2011). Co-infections of Plasmodium knowlesi, P. falciparum, and P. vivax among humans and Anopheles dirus mosquitoes, Southern Vietnam. Emerging Infectious Diseases, 17(7), 1232–1239. https://doi.org/10.3201/eid1707.101551 Marrelli, M. T., & Brotto, M. (2016). The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles. Malaria Journal, 15(1), 1–6. https://doi.org/10.1186/s12936-016-1577-y Martinsen, E. S., Perkins, S. L., & Schall, J. J. (2008). A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): evolution of life-history traits and host switches. Molecular Phylogenetics and Evolution, 47(1), 261–273. https://doi.org/10.1016/j.ympev.2007.11.012 Miller, K. D., White, N. J., Lorr, J. A., Roberts, J. M., & Greenwood, B. M. (1989). Biochemical evidence of muscle injury in african children with severe malaria. Journal of Infectious Diseases, 159(1), 139–142. https://doi.org/10.1093/infdis/159.1.139 Ministry of Health Malaysia. (2013). Management guidelines of malaria Malaysia. Mohd-Azlan, J., Messerli, Z., & Cheok, M. (2017). Habitat occupancy and activity patterns of the long-tailed macaques and pig-tailed macaques in Sarawak, Borneo. Malayan Nature Journal, 69(4), 277–285. Morse, S. S. (1995). Factors in the emergence of infectious diseases. Emerging Infectious Diseases, 1(1), 7–15. https://doi.org/10.3201/eid0101.950102 Moyes, C. L., Shearer, F. M., Huang, Z., Wiebe, A., Gibson, H. S., Nijman, V., Mohd-Azlan, J., Brodie, J. F., Malaivijitnond, S., Linkie, M., Samejima, H., O’Brien, T. G., Trainor, C. R., Hamada, Y., Giordano, A. J., Kinnaird, M. F., Elyazar, I. R. F., Sinka, M. E., Vythilingam, I., … Hay, S. I. (2016). Predicting the geographical distributions of the macaque hosts and mosquito vectors of Plasmodium knowlesi malaria in forested and non-forested areas. Parasites & Vectors, 9(242). https://doi.org/10.1186/s13071-016-1527-0 Müller, M., & Schlagenhauf, P. (2014). Plasmodium knowlesi in travellers, update 2014. International Journal of Infectious Diseases, 22, 55–64. https://doi.org/10.1016/j.ijid.2013.12.016 Ooi, C. H., Bujang, M. A., Tg Abu Bakar Sidik, T. M. I., Ngui, R., & Lim, Y. A. L. (2017). Over two decades of Plasmodium knowlesi infections in Sarawak: Trend and forecast. Acta Tropica, 176(June), 83–90. https://doi.org/10.1016/j.actatropica.2017.07.027 Pain, A., Böhme, U., Berry, A. E., Mungall, K., Finn, R. D., Jackson, A. P., Mourier, T., Mistry, J., Pasini, E. M., Aslett, M. A., Balasubrammaniam, S., Borgwardt, K., Brooks, K., Carret, C., Carver, T. J., Cherevach, I., Chillingworth, T., Clark, T. G., Galinski, M. R., … Berriman, M. (2008). The genome of the simian and human malaria parasite Plasmodium knowlesi. Nature, 455(7214), 799–803. https://doi.org/10.1038/nature07306 Perkins, S. L. (2000). Species concepts and malaria parasites: Detecting a cryptic species of Plasmodium. Proceedings of the Royal Society B: Biological Sciences, 267(1459), 2345–2350. https://doi.org/10.1098/rspb.2000.1290 Perkins, S. L. (2014). Malaria’s many mates: Past, present, and future of the systematics of the order Haemosporida. Journal of Parasitology, 100(1), 11–25. https://doi.org/10.1645/13-362.1 Pinheiro, M. M., Ahmed, M. A., Millar, S. B., Sanderson, T., Otto, T. D., Lu, W. C., Krishna, S., Rayner, J. C., & Cox-Singh, J. (2015). Plasmodium knowlesi genome sequences from clinical isolates reveal extensive genomic dimorphism. PLoS ONE, 10(4), 1–16. https://doi.org/10.1371/journal.pone.0121303 Pongvongsa, T., Culleton, R., Ha, H., Thanh, L., Phongmany, P., Marchand, R. P., Kawai, S., Moji, K., Nakazawa, S., & Maeno, Y. (2018). Human infection with Plasmodium knowlesi on the Laos-Vietnam border. Tropical Medicine and Health, 46(1), 1–6. https://doi.org/10.1186/s41182-018-0116-7 Ponnappan, S., & Ponnappan, U. (2011). Aging and Immune Function: Molecular Mechanisms to Interventions. Antioxidants & Redox Signaling, 14(8), 1551–1585. https://doi.org/10.1089/ars.2010.3228 Ramírez, J. F., Porras, B., Borrero, E., & Martínez, S. P. (2016). Factors associated with the severity and complication of patients with malaria hospitalized between 2009 and 2013 in three municipalities of Colombia, case control study. Malaria Journal, 15(1), 1–9. https://doi.org/10.1186/s12936-016-1554-5 RStudio Team. (2016). RStudio: Integrated development for R. RStudio, Inc. Sallum, M. A. M., Peyton, E. L., Harrison, B. A., & Wilkerson, R. C. (2005). Revision of the Leucosphyrus group of Anopheles (Cellia) (Diptera, Culicidae). Revista Brasileira de Entomologia, 49(SUPPL. 1), 1–152. https://doi.org/10.1590/s0085-56262005000500001 Schmidt, L. H., Greenland, R., & Genther, C. S. (1961). The transmission of Plasmodium cynomolgi to man. The American Journal of Tropical Medicine and Hygiene, 10(5), 679–688. https://doi.org/10.4269/ajtmh.1961.10.679 Schrag, S. J., & Wiener, P. (1995). Emerging infectious disease: what are the relative roles of ecology and evolution? Trends in Ecology & Evolution, 10(8), 319–324. https://doi.org/10.1016/S0169-5347(00)89118-1 Semenya, A. A., Tran, T. M., Meyer, E. V., Barnwell, J. W., & Galinski, M. R. (2012). Two functional reticulocyte binding-like (RBL) invasion ligands of zoonotic Plasmodium knowlesi exhibit differential adhesion to monkey and human erythrocytes. Malaria Journal, 11(228). https://doi.org/10.1186/1475-2875-11-228 Silal, S. P., Barnes, K. I., Kok, G., Mabuza, A., & Little, F. (2013). Exploring the seasonality of reported treated malaria cases in Mpumalanga, South Africa. PloS One, 8(10), 1–9. https://doi.org/10.1371/journal.pone.0076640 Singh, B., Bobogare, A., Cox-Singh, J., Snounou, G., Abdullah, M. S., & Rahman, H. A. (1999). A genus- and species-specific nested polymerase chain reaction malaria detection assay for epidemiologic studies. The American Journal of Tropical Medicine and Hygiene, 60(4), 687–692. https://doi.org/10.4269/ajtmh.1999.60.687 Singh, B., & Daneshvar, C. (2013). Human infections and detection of Plasmodium knowlesi. Clinical Microbiology Reviews, 26(2), 165–184. https://doi.org/10.1128/CMR.00079-12 Singh, B., Lee, K. S., Matusop, A., Radhakrishnan, A., Shamsul, S. S. G., Cox-Singh, J., Thomas, A., & Conway, D. J. (2004). A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet, 363(9414), 1017–1024. https://doi.org/10.1016/S0140-6736(04)15836-4 Sinha, A., Hughes, K. R., Modrzynska, K. K., Otto, T. D., Pfander, C., Dickens, N. J., Religa, A. A., Bushell, E., Graham, A. L., Cameron, R., Kafsack, B. F. C., Williams, A. E., Llinas, M., Berriman, M., Billker, O., & Waters, A. P. (2014). A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature, 507(7491), 253–257. https://doi.org/10.1038/nature12970 Snipes, M., & Taylor, D. C. (2014). Model selection and Akaike Information Criteria: An example from wine ratings and prices. Wine Economics and Policy, 3(1), 3–9. https://doi.org/10.1016/j.wep.2014.03.001 Snounou, G., Viriyakosol, S., Xin Ping Zhu, Jarra, W., Pinheiro, L., do Rosario, V. E., Thaithong, S., & Brown, K. N. (1993). High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Molecular and Biochemical Parasitology, 61(2), 315–320. https://doi.org/10.1016/0166-6851(93)90077-B Srivastava, K., Sharma, M., & Mitchell, W. B. (2017). Infection & inflammatory diseases malaria and thrombopoiesis : A possible mechanism for the malarial thrombocytopenia. Journal of Immunology, Infection and Inflammatory Diseases, 2(3), 1–6. www.scientonline.org Ta Tang, T.-H., Salas, A., Ali-Tammam, M., Martinez, M. del C., Lanza, M., Arroyo, E., & Rubio, J. M. (2010). First case of detection of Plasmodium knowlesi in Spain by Real Time PCR in a traveller from Southeast Asia. Malaria Journal, 9(219), 1–6. https://doi.org/10.1186/1475-2875-9-219 Tan, C. H., Vythilingam, I., Matusop, A., Chan, S. T., & Singh, B. (2008). Bionomics of Anopheles latens in Kapit, Sarawak, Malaysian Borneo in relation to the transmission of zoonotic simian malaria parasite Plasmodium knowlesi. Malaria Journal, 7, 1–8. https://doi.org/10.1186/1475-2875-7-52 Taylor, W. R. J., Hanson, J., Turner, G. D. H., White, N. J., & Dondorp, A. M. (2012). Respiratory manifestations of malaria. Chest, 142(2), 492–505. https://doi.org/10.1378/chest.11-2655 Thanachartwet, V., Krudsood, S., Tangpukdee, N., Phumratanaprapin, W., Silachamroon, U., Leowattana, W., Wilairatana, P., Brittenham, G. M., Looareesuwan, S., & Neild, G. H. (2008). Hyponatraemia and hypokalaemia in adults with uncomplicated malaria in Thailand. Tropical Doctor, 38(3), 155–157. https://doi.org/10.1258/td.2007.070112 Tsukamoto, M., Miyata, A., & Miyagi, I. (1978). Surveys on simian malaria parasites and their vector in Palawan Island, the Philippines. Tropical Medicine, 20(1), 39–50. Tyagi, R. K., Das, M. K., Singh, S. S., & Sharma, Y. D. (2013). Discordance in drug resistance-associated mutation patterns in marker genes of Plasmodium falciparum and Plasmodium knowlesi during coinfections. Journal of Antimicrobial Chemotherapy, 68(5), 1081–1088. https://doi.org/10.1093/jac/dks508 Van den Steen, P. E., Deroost, K., Deckers, J., Van Herck, E., Struyf, S., & Opdenakker, G. (2013). Pathogenesis of malaria-associated acute respiratory distress syndrome. Trends in Parasitology, 29(7), 346–358. https://doi.org/10.1016/j.pt.2013.04.006 Van Hellemond, J. J., Rutten, M., Koelewijn, R., Zeeman, A. M., Verweij, J. J., Wismans, P. J., Kocken, C. H., & Van Genderen, P. J. J. J. (2009). Human Plasmodium knowlesi infection detected by rapid diagnostic tests for malaria. Emerging Infectious Diseases, 15(9), 1478–1480. https://doi.org/10.3201/eid1509.090358 Van Wolfswinkel, M. E., Hesselink, D. A., Zietse, R., Hoorn, E. J., & Van Genderen, P. J. J. (2010). Hyponatraemia in imported malaria is common and associated with disease severity. Malaria Journal, 9(1), 1–8. https://doi.org/10.1186/1475-2875-9-140 Vandermosten, L., Pham, T. T., Possemiers, H., Knoops, S., Van Herck, E., Deckers, J., Franke-Fayard, B., Lamb, T. J., Janse, C. J., Opdenakker, G., & Van Den Steen, P. E. (2018). Experimental malaria-associated acute respiratory distress syndrome is dependent on the parasite-host combination and coincides with normocyte invasion. Malaria Journal, 17(1), 1–17. https://doi.org/10.1186/s12936-018-2251-3 Vythilingam, I., & Hii, J. (2013). Simian Malaria Parasites: Special Emphasis on Plasmodium knowlesi and Their Anopheles Vectors in Southeast Asia. In S. Manguin (Ed.), Anopheles mosquitoes - New insights into malaria vectors. InTech. https://doi.org/10.5772/54491 Vythilingam, I., Wong, M. L., & Wan-Yussof, W. S. (2018). Current status of Plasmodium knowlesi vectors: a public health concern? Parasitology, 145(1), 32–40. https://doi.org/10.1017/S0031182016000901 Warrell, D. A., & Gilles, H. M. (2002). Essential Malariology (3rd ed.). CRC Press. Warren, M., Cheong, W. H., Fredericks, H. K., & Coatney, G. R. (1970). Cycles of jungle malaria in West Malaysia. The American Journal of Tropical Medicine and Hygiene, 19(3), 383–393. https://doi.org/10.4269/ajtmh.1970.19.383 Warren, M., & Wharton, R. H. (1963). The vectors of simian malaria: identity, biology and geographical distribution. The Journal of Parasitology, 49(6), 892–904. https://doi.org/10.2307/3275715 Waters, A. P., & McCutchan, T. F. (1989). Rapid, sensitive diagnosis of malaria based on ribosomal RNA. Lancet (London, England), 1(8651), 1343–1346. https://doi.org/10.1016/s0140-6736(89)92800-6 Wharton, R. H., & Eyles, D. E. (1961). Anopheles hackeri, a vector of Plasmodium knowlesi in Malaya. Science, 134(3474), 279–280. https://doi.org/10.1126/science.134.3474.279 Wharton, R. H., Eyles, D. E., Warren, M., & Cheong, W. H. (1964). Studies to determine the vectors of monkey malaria in malaya. Annals of Tropical Medicine and Parasitology, 58(1), 56–77. https://doi.org/10.1080/00034983.1964.11686215 White, N. J. (2008). Plasmodium knowlesi: The Fifth Human Malaria Parasite. Clinical Infectious Diseases, 46(2), 172–173. https://doi.org/10.1086/524889 White, N. J. (2009). Malaria. In C. GC & Z. AI (Eds.), Manson’s Tropical Diseases (22nd ed., pp. 532–600). Saunders Ltd. https://doi.org/10.1016/S0140-6736(18)30324-6 White, N. J. (2018). Anaemia and malaria. Malaria Journal, 17(371). https://doi.org/10.1186/s12936-018-2509-9 White, N. J., Pukrittayakamee, S., Hien, T. T., Faiz, M. A., Mokuolu, O. A., & Dondorp, A. M. (2014). Malaria. The Lancet, 383(9918), 723–735. https://doi.org/10.1016/S0140-6736(13)60024-0 WHO. (2020). World Malaria Report 2020: 20 years of global progress and challenges. Licence: CC BY-NC-SA 3.0 IGO. WHO | Zoonoses. (2017). WHO. https://www.who.int/topics/zoonoses/en/ William, Timothy, Jelip, J., Menon, J., Anderios, F., Mohammad, R., Awang Mohammad, T. A., Grigg, M. J., Yeo, T. W., Anstey, N. M., & Barber, B. E. (2014). Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi. Malaria Journal, 13(1), 390. https://doi.org/10.1186/1475-2875-13-390 William, T., Rahman, H. A., Jelip, J., Ibrahim, M. Y., Menon, J., Grigg, M. J., Yeo, T. W., Anstey, N. M., & Barber, B. E. (2013). Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax malaria in Sabah, Malaysia. PLoS Neglected Tropical Diseases, 7(1), e2026. https://doi.org/10.1371/journal.pntd.0002026 Willmann, M., Ahmed, A., Siner, A., Wong, I., Woon, L., Singh, B., Krishna, S., & Cox-Singh, J. (2012). Laboratory markers of disease severity in Plasmodium knowlesi infection: a case control study. Malaria Journal, 11(363). https://doi.org/10.1186/1475-2875-11-363 Wolfe, N. D., Dunavan, C. P., & Diamond, J. (2007). Origins of major human infectious diseases. Nature, 447(7142), 279–283. https://doi.org/10.1038/nature05775 Wong, M. L., Chua, T. H., Leong, C. S., Khaw, L. T., Fornace, K., Wan-Sulaiman, W.-Y., William, T., Drakeley, C., Ferguson, H. M., & Vythilingam, I. (2015). Seasonal and Spatial Dynamics of the Primary Vector of Plasmodium knowlesi within a Major Transmission Focus in Sabah, Malaysia. PLoS Neglected Tropical Diseases, 9(10), e0004135. https://doi.org/10.1371/journal.pntd.0004135 World Health Organization (WHO). (2014). Severe malaria. Tropical Medicine & International Health, 19(10), 7–131. https://doi.org/10.1111/tmi.12313_2 World Health Organization (WHO). (2015). Guidelines for the treatment of malaria (3rd ed.). Yasuoka, J., & Levins, R. (2007). Impact of deforestation and agricultural development on anopheline ecology and malaria epidemiology. American Journal of Tropical Medicine and Hygiene, 76(3), 450–460. Yuda, M., Iwanaga, S., Shigenobu, S., Mair, G. R., Janse, C. J., Waters, A. P., Kato, T., & Kaneko, I. (2009). Identification of a transcription factor in the mosquito-invasive stage of malaria parasites. Molecular Microbiology, 71(6), 1402–1414. https://doi.org/10.1111/j.1365-2958.2009.06609.x Yusof, R., Lau, Y., Mahmud, R., Fong, M., Jelip, J., Ngian, H., Mustakim, S., Mat Hussin, H., Marzuki, N., & Mohd Ali, M. (2014). High proportion of knowlesi malaria in recent malaria cases in Malaysia. Malaria Journal, 13(168). https://doi.org/10.1186/1475-2875-13-168 Zhang, Z. (2016). Variable selection with stepwise and best subset approaches. Annals of Translational Medicine, 4(7), 1–6. https://doi.org/10.21037/atm.2016.03.35