Malaria duetoPlasmodiumknowlesi Recibido: 05/10/2009 lsoim knowlesi Plasmodium America), humans: for they are agents infectious have potential them as of documented five been monkeys, infect may plas which twenty species the modia Among humans. to transmission malaria for infesta simian common by a and tion of presence human in evident, of envi becomes overlapping these habitats In an factors. contexts, risk ronmental epidemiological interest further are vil bear activities in when ed, breeding especially or also agricultural forests, of which rain living to lages America, close Southern areas wild and volved Asia demo Southern present of regions the different the in populations Moreover, local of origin. expansion graphic simian malaria of acquire to travellers elements risk plasmodia of increase by objective expected an to represent visited lead which activities, increasingly trekking are practicing which and zones regions, started), forest recently wild (i.e. been have past activities the productive where in anthropized poorly which America areas remained in geographic in Central-Southern activities occurred human and of expansion The predominantly China, protozoa Asia, plasmodia South-Eastern transmission The these concerns. health of public minor rare with a recently event, until considered been has humans to mon ganisms infecting of capable ( are keys eras plasmodia Neolithic malaria of of species beginning the Me of and end the solithic between probably it monkeys by since acquired evolution, was their during later humans by encountered evolu species human (co-evolution) tion the paralelling evolution older an had beings. human involve vivax modium plasmodia malaria main Four Key words: parasites, Malaria Plasmodiumknowlesi, emergingplasmodia,humanhealth,public healthconcerns Telephone: +39-051-6363355. Telefax: +39-051-343500. Infectious Diseases, S. OrsolaHospital. Via Massarenti11. I-40138Bologna,Italy Dr. SergioSabbatani, MD Correspondence: Conflicts ofinterest,funding,sponsorship, acknowledgements: none 2 1 Sergio Sabbatani Plasmodium knowlesi asthefifthmalariaparasite a healthcarealert? May casesrepresent imported in South-EasternAsiaandAmerica. Internal Medicine,General Hospital,Budrio, Budrio Internal Italy Infectious Diseases, University ofBologna,S. Orsola-Malpighi Hospital,Bologna,Italy al 1 Table Anopheles Plasmodium simium, Plasmodium brasilianum lsoim yoog, lsoim inui Plasmodium cynomolgi, Plasmodium 1 , MD, Fiorino Sirio , , u te ncoa tasiso o tee or these of transmission anecdotal the but ), Plasmodium malariae malariae Plasmodium 1-3 oqios wih r te edd vehicle needed the are which mosquitoes, while , SuhEsen Asia) (South-Eastern Aceptado: 05/10/2009 lsoim falciparum Plasmodium 2 , MD, Manfredi Roberto and Plasmodium ovale Plasmodium E-mail: [email protected] 5 Te aoiy of majority The . 1 , MD 4 . Over twenty twenty Over . a been has (South and , Plas 5 ------. rain forest (1.85%) and the examined longhouses (the typical typical (the longhouses examined the and the (1.85%) regards forest frequency rain reduce a while (6.74%), forest of limits latens vec efficient more the transmitting tor context geographic con Malaysian parasite the in blood elevated so centrations reaches quartan never so-called the and of fever), (responsible days three every therefore cycle may whereas of and treatment, absence effective in an cycle parasitemia life-threatening replication elevated, an daily reach a has modium of with assessed by similar infected those morphologically to proved erythrocytes whose subjects specific of esi evolu availability lethal the a Later, with present. were cases tion four also authors these administered of records not was rap treatment a appropriate should and course, id clinical of elevated severity the the was and patients parasitemia a these of received feature distinctive but A tion. course, of malaria diagnosis (microscopic) typical microbiological a presented health which international the of authorities recently care more and Asia, Eastern South- in operating clinicians century and XXI researchers of early attention and the century between past the Malaysia) of end (peninsular the Pahang Malaysia the and to belonging Confederation), in state Sarawak (a Sabah techniques Boneo), biomolecular (Malaysian by confirmed foci ease of of identification are The neglected. they or missed sinceten chemotherapy, and self-limiting, antimalaric frequently requires is rarely which humans, in mild-to-moder disease a ate cause to tend monkeys of infection malaria P. knowlesi primers allowed to pose a definitive diagnosis also in also diagnosis definitive a pose to allowed primers ad h ms eeae bt rt i rgsee a the at registered is rate bite elevated most the and , 6-8 Rcn etmlg studies entomology Recent . . malariae P. malaria is related to the evidence that this Plas this that evidence the to related is malaria 5 P. knowlesi iiily ouig h atnin n episodes on attention the focusing initially , . malariae P. primers. The more severe impact impact severe more The primers. infection to humans is humans to infection . malariae P. bt etd eaie when negative tested but , 9 eotae that demontrated . malariae P. a a replication a has P. knowlesi Anopheles 6,7 . knowl P. 6,7 catched , i the in ; infec dis ------

48 Archivos Venezolanos de Farmacología y Terapéutica Volumen 28, número 2, 2009 Malaysia houses) (0.28%), which never were the site of mi- tic-identification problems, may confuse Western health care cro-epidemic disease clusters. Based on these data, it has providers, especially when a basic microscopic, parasito- been hypothesized that humans acquire infection in the for- logic examination is carried out for the research and identifi- est, when hunting, or after working hours, when coming cation of malaria plasmodia, which does not allow to distin- home at darkness10. The potential simian reservoirs are guish P. malariae from P. knowlesi, therefore posing at risk Macaca mulatta, M. nemestina, M. inus, and Saimiri sciurea. patient’s life8. The biomolecular techniques are extremely After the report of Malaysia foci, where native population was useful to trace the general epidemiology of malaria, and to involved, and the identification of single imported cases in clarify the role and importance of mixed infections, which still Europe and North America by tourists who travelled for short remain underestimated8. Unfortunately these sophisticated periods close to forest areas of South-Eastern Asia11-15, the assays are costly and not easily available throughout the attention of researchers for P. knowlesi rapidly increased. In world, especially in developing countries. On the basis of the year 2008, the Journal “Nature” published the analysis of epidemiological features of regions where epidemic foci of P. the nuclear genomic sequencing of P. knowlesi16. It was the knowlesi malaria have been reported, and the anecdotal first complete gene sequencing of a simian Plasmodium, episodes of clinical reports occurred in Western travellers therefore offering the opportunity for a comparation with the coming back in their countries of origin with a P. knowlesi complete genome of P. vivax and other already known Plas- disease, it is not possible to establish whether infections modia genomes. In contrast with other plasmodial genomes, have been acquired by the most common animal reservoirs putative familiar antigenic variants are scattered throughout (i.e. macaques), or whether human-to-human contagion may the genome and associated with intrachromosomal telomere occur. However, it is presently clear that this zoonosis is no repeats. One of these families, called KIRs, includes genom- more responsible of single, episodic cases, but it represents ic sequences which on the whole match around one-half of a true health care emrgency in South-Eastern Asian coun- the extracellular domain CD99 of the host: this situation sug- tries. The Figure 1 allows to appreciate the overal co-evolu- gested that this form could represent an inusual molecular tive pathway of malaria plasmodia in parallel with that of the mimicry16,17. A relevant information came from recent obser- genus Homo, from hominids (group A), toward modern men vations and epidemiological data coming from Malaysia. The (group C), with the appearance of P. falciparum which en- habitat of humans is more and more overlapping that of pri- tered the epidemiological scenario infecting humans (group mates, and it is primarily due to two aspects: the first is re- B) of mesolithic and early neolithic eras, who spent their lives lated to the expansion of human activities (agriculture, defor- in cabins located at the edge of rain forest and in the proxim- esting, clearing of valued wood, and animal breeding), in ity of the first cultured fields. Just the introduction of the first areas also inhabitated by monkeys. The second emerging organized human activities which significantly contributed to issue is related to the relevant increase of touristic activities the expansion of P. falciparum, which up to date represents (i.e. trekking) by intrenational visitors, who spend a propor- the most relevant malaria pathogen from the pathocenosis of tionally limited time in this environment, and subsequently pre-historical populations, unavoidably conditioning both come back to their countries of origin8. In this last situation, economic and anthropological development. With regard to the limited knowledge of simian plasmodia and thir diagnos- the appearance of a novel malaria parasite epidemiologi-

Table 1

49 Simian Plasmodium species Human species resembling to them Regional distribution Asia P. coatney P. falciparum Malaysia, Philippines P. cynomolgi P. vivax India, Indonesia, Malaysia, Sri Lanka, Taiwan P. eylesi P. vivax Malaysia P. fieldi P. ovale Malaysia P. fragile P. falciparum India, Sri Lanka P. hylobati P. vivax Indonesia P. inui P. malariae India, Indonesia, Malaysia, Philippines, Sri Lanka, Taiwan P. jeffrey P. vivax Indonesia, Malaysia

P. knowlesi P. malariae, P. falciparum China, Indonesia, Malaysia, Philippines, Singapore, Thailand, Taiwan

P. pitheci P. vivax Malaysia P. simiovale P. ovale Sri Lanka P. silvaticum P. vivax Malaysia P. youngi P. vivax Malaysia South America P. brasilianum P. malariae Brazil, Colombia, Mexico, Panama, Peru, Venezuela P. simium P. vivax Brazil Malaria species of simian origin isolated in Asia and in Southern America (modified from the reference quotation4). Their associated geographical distrubution, and the morphologic similarities to one of the four “classical” human plasmodia species (i.e. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae), are pointed out. 9. 8. 7. 6. 5. 4. 3. 2. 1. lished by L.Capasso (quoted at reference ofgroup parasites. withtheadjunct Cmalaria [1]),inparticular outintheforestto carried productive andtouristic humanactivities regions ofMalaysia andBorneo. The imagehasbeentakenandmodifiedfrom somestudiespub tion pathway of The thebiological enclosedgraph andfilogeneticalevolutions depicts of se particularly for responsible be may infancy, early occur during normally which contacts the not after populations, In immunized, autochtonous naturally features. of environmental impact and the evenience, climatic this similar to suscep due are which tible areas, other to South-East extension without of Asia, countries ern some in patoce circumscribed novel remain this that nosis is hope the humans, for relevant cally References Figure 1

e ltn i Srwk Mlyi. rn R o To Md y 2006; Hyg Med Trop Soc R Trans Malaysia. 100:1987-1088. Anophe Sarawak, by in humans latens to les knowlesi Plasmodium of transmission tural Editorial Commentary. Dis2008;46:172-173. ClinInfect 46:165- 2008; Dis Infect Clin threatening. 171. distribu lifre widely potentially is humans and in ted malaria knowlesi Plasmodium al. et S, 363:1017- 2004; Plasmo Lancet acquired beings. naturally 1024. human of in focus infections large knowlesi A dium al. et J, Cox-Singh SG, in aUStraveler. MMWR2009;58:229-232. of Agriculture. Academic Press Inc.,Orlando, 1984. Greenwood Press, Westport, 1963. Wiley &Sons, New York, 1985. yhigm , a C, sa M Ca S, e K, ig B Na B. Singh KS, Lee ST, Chan M, Asmad CH, Tan I, Vythlingam parasite. malaria human fifth the knowlesi: Plasmodium NJ. White Ratnam A, Matusop SGS, Shamsul KS, Lee TME, Davis J, Cox-Singh Smita Shamsul A, Radhakrishnama A, Matusop LK, Sung B, Sing malaria Simian (CDC). Prevention and Control Disease for Centers Originis the at Paleopathology In: (Eds.). GJ Armelagos MN, Cohen Diseases. Infections of Eradication and Evolution The A. Cockburn John Mammals. and Arthropods Parasitic of Coevolution KC. Kim Capasso L.L’origine dellemalattie. Chieti,Italy, M.Solfanelli, 1985 P. falciparum (group B). P. knowlesi (belonging to isthelast group C), P. vivax , P. malariae Plasmodium ------aai ifcin woe igoi cno rl o te routine the examinations.laboratory on rely cannot a diagnosis with whose origin infection, of malaria countries their to risk back the come to to exposed be may who excursionists, number and the growing tourists for of also but of memery, lacking immune populations specific a local for only not consequences, vere 17. 16. 15. 14. 13. 12. 11. 10. , and

h gnm o te iin n hmn aai prst Plasmodium parasite malaria human knowlesi.Nature 2008;455:799-803. and simian the of genome The Plasmo parasite human dium vivax. Nature 2008;455:757-763. neglected the of genomics Comparative al. Malaria Borneo. Malaysian visiting 2009;8:15:1-5. PlaJournal after with traveller malaria Swedish knowlesi B. Singh smodium A, Färnert PCS, Divis V, Bronner al. et PS, Singapo Wong NL,infection, re. Dis2008;14:814-816. Emerg Infect knowlesi Ching LP, Plasmodium Jarrod human LC, acquired Chuan Naturally OE, Eong OT, Ng Bing Chong Sheng Ji Yu Xue Za Zhi2006;24:70-71. Chong Sheng Ji Zhongguo knowlesi. Thailand. human, in malaria Dis2004;10:2211-2213. Emerg Infect knowlesi Plasmodium acquired turally Dis Infect Emerg Malaysia. from 2008; 14:1434-1436. returning traveller European an in relation Plasmodium parasite in malaria Borneo J2008;7:52-59. Malaria knowlesi. simian zoonotic Malaysian of transmission Sarawak, the Kapit, to in latens Anopheles an , öm U Bry E Mnal , in D Jcsn P e al. et AP, Jackson RD, Finn K, Mungall AE, Berry U, Böhme A, Pain et E, Caler H, Lorenzi SL, Bidwell JC, Slva JH, Adams JM, Carlton Plasmodium of infection natural Human H. Zheng J, Li HM, Zhu Na H. Kambara T, Sata T, Iwasatit C, Putaporntip S, Jongwutiwes malaria Monkey ST. Jokiranta D, Müller I, Felger H, Marti A, Kantele of Bionomics B. Singh ST, Chan A, Matusop I, Vythlingam CH, Tan P. specieswhichsteadily entered thehumanpathology, andisrelated

ovale (Group A), compared withtheextremelymore recent evolu - . knowlesi P. - - - - -

50 Archivos Venezolanos de Farmacología y Terapéutica Volumen 28, número 2, 2009