ParaSites Project

Winter 2009

 

Parasite - Plasmodium Knowlesi

 

Introduction

 

            Plasmodium knowlesi is the fifth major species of malaria. This is an emerging infection that was reported for the first time in humans in 1965[1]. It accounts for up to 70% of malaria cases in South East Asia where it is mostly found[2]. This disease is transmitted by the bite of an Anopheles lucosphyrus mosquito. Malaria knowlesi has health, social and economic consequences for the regions affected by it.

 

Anopheles Mosquito, http://www.gasdetection.com/news2/anopheles_mosquito_4_hnd.jpg

 

 

Epidemiology/ Regions of incidence

 

            Plasmodium knowlesi is mostly found in South East Asian countries particularly in Borneo, Singapore, Philippines, Malaysia, Myanmar, Thailand and other neighboring countries.

            Although the overall current infection rate with malaria knowlesi is relatively low, one risk it poses is its ability to be misdiagnosed with other more benign forms of malaria such as P. malariae[3] especially when microscopy is used. P. knowlesi is more accurately distinguished from P. malariae using PCR assay and molecular characterization. Another problem posed by this parasite is its ability to multiply rapidly within a short amount of time resulting in very high parasite densities within the body, which can be fatal[4].

            Found mostly in South East Asia (see list of countries above). Endemic to this region but infective mosquitoes are restricted to the forest areas. Non-infective mosquitoes are typically found in the urban areas. Transmission is constant due to abundance of the Anopheles l. Malaria knowlesi appears to occur in regions that are reportedly free of the other four types of human malaria.

            There are four possible modes of transmission (see above) Gametocytes can be seen in the blood between 10 - 12 days of infection.

            Malaria knowlesi is less prevalent in Africa because it appears that West African blacks are les likely to be infected by malaria knowlesi. This seems to be the case because many West African blacks have Duffy-negative blacks.

 

Morphology

 

Morphology, http://www.tulane.edu/~wiser/protozoology/notes/images/pl_sp.gif

 

 

 

 

Agent (Classification and taxonomy)

 

Kingdom - Protista

Sub Kingdom - Protozoa

Phylum - Apicomplexa

Class - Sporozoasida

Order – Eucoccidiorida

Family – Plasmodiidae

Genus – Plasmodium

Species - knowlesi

 

Disease causing Agent - Plasmodium knowlesi.

 

History of Discovery

 

            In 1931, malaria knowlesi was recognized for the first time as a disease of long tailed macaques. It was a lethal disease for these monkeys[5]. From early in the 1930s, P. knowlesi was use as a pyretic treatment for patients who were sick with neurosyphillis[6].  In 1932 – an inoculation experiment using human blood revealed that the disease could also infect humans[7]. In 1965, the first case of a natural infection of malaria knowlesi in humans was reported in an American man who had returned from visiting peninsular Malaysia[8]. The infecting parasite was initially identified as P. Falciparum, one day later, it was identified as P. malariae and it was only confirmed to be P. knowlesi after the infected blood was used to inoculate Rhesus monkeys[9]. A second report emerged in 1971 about the natural infection of a man in Malaysia with malaria knowlesi[10]. However, since 2004, there have been an increased number of reports in the incidence of malaria knowlesi among humans in South East Asia[11].

 

 

Clinical Presentation in Humans

 

            Symptoms of malaria knowlesi in humans include headache, fever, chills and cold sweats[12]. In addition to a lab diagnosis using PCR array, Malaria knowlesi could also present itself with elevated levels of  C-reactive protein and thrombocytopenia in the patient.[13]

 

 

Diagnosis and Diagnostic Tests

 

            There are several methods for detecting and diagnosing malaria knowlesi. At the moment, PCR assay and molecular characterization are the most reliable methods for detecting P. knowlesi[14]. PCR identifies the parasite protein but this technique is not rapid and cannot be used for routine identification. PCR is also expensive and requires very specialized equipment[15]. Rapid diagnostic tests kits may or may not recognize the malaria knowlesi parasite because of its specificity. Microscopy techniques can also be used to detect the presence of the P. knowlesi parasite in erythrocytes however this technique is not reliable because P. knowlesi can also be confused with P. malariae because of their morphological similarities.

 

 

Transmission

 

            Plasmodium knowlesi is frequently transmitted by the Anopheles leucosphyrus mosquito, which lives in forested areas of South East Asia[16]. The disease was typically found among macaques. However the disease can be transmitted through the bite of an infected Anopheles leucosphyrus mosquito. One infective bite in humans in sufficient to cause disease manifestation in humans. This mosquito injects sporozoites into its human host[17]. The invasion mechanism of the parasite appears to be aided through the help of the ligand duffy glycoprotein found on the surface of the plasmodium knowlesi parasite[18].

            With the increasing popularity of deforestation and development efforts in South East Asia, many macaques are now coming in close and direct contact with humans[19] Hence more and more people who live in the semi-urban areas are testing positive for Malaria knowlesi

            There are four known techniques via which the plasmodium knowlesi parasite can infect. The four modes are a mosquito bite from an infected monkey to another monkey, from an infected monkey to a human, from an infected human to another human and from an infected human back to a monkey[20].

 

 

Pathogenesis

 

            Symptoms typically begin approximately 11 days after the anopheles leucophyrus mosquito has bitten a person[21]. 

 

 

 

Treatment

 

            Malaria knowlesi is most effectively treated if the infection is detected early. P. Knowlesi takes only 24 hours to complete its life cycle, which means it can result in very high parasite density in a short amount of time, which can be fatal in humans[22]. However,

the disease can be treated using already existing anti-malaria therapy such as mefloquine and chloroquine. Chloroquine is specifically preferred for non-complictaed infections[23].

 

Mefloquine tablets http://shop.interhealth.org.uk/products/images/l/m4b.jpg

 

 

 

 

 

Reservoir

 

 

 

         Long and Pig tailed Macaques found in South east asian countries such as Malaysia[24]. Particularly the M. fascicularis and Macaca nemestrina species[25].

 

 

Vector

            An Infected Anopheles leucosphyrus mosquito is the vector that transmits P. Knowlesi from monkeys to humans. This mosquito typically lives in forest areas in south East Asia but with a greater clearing of forest areas for farmland, more humans are increasingly becoming exposed to this vector. Another species of mosquitoes, Anopheles crucens has been purportedly cited as a vector of malaria knowlesi. Both species of mosquitoes have been to contain as many as 1,000 sporozoites suggesting that they are efficient vectors[26].  Anopheles lateens has also been cited as the vector for malaria knowlesi in Malaysia[27].

 

Incubation Period

 

Incubation period for malaria knowlesi is about 12 days[28]. P. knowlesi is the shortest known malaria of all the known malarias that infect humans and primates[29]. P knowlesi has a 24 hour asexual cycle

 

 

 

 

Life cycle

 

            The Plasmodium knowlesi parasite replicates and completes its blood stage cycle in 24 hour cycles[30] resulting in failr hgh loads of parasite densities ina very  short period of time. This makes it a potentially very severe disease if it remains untreated.. Length of life cycle?

 

Gametocyte schizo t Trophozoites (These stages are microscopically indfferentiabe from plasmodium malariae using microscopy.

 

 

 

The human blood stage takes 24 hours to complete its asexual life cycle. This is the fastest life cycle for a human plasmodium parasite.

 

 

 

 

 

 

 


In Mosquito:

                         

The mosquito ingests Gametocyte, which mature into Microgametes. These microgametes mature into Macrogametes and then into Zygotes.  Eventually, the zygotes mature into Ookinete, which also mature into Oocysts. Finally, the oocyts mature into sporozoites and they travel to salivary gland of the mosquito

 

Gametocyte Microgametes Macrogamete Zygote Ookinete Oocyst Sporozoite

 

 

In Man:

 

Sporozoites  Trophozoites Schizonts Merozoites (Hypnozoites) Gametocytes

 

The Sporozoites are injected into humans and they undergo asexual reproduction to become Hypnozoites. This Hypnozoite undergoes sexual reproduction and becomes the Gametocyte becomes sporozoite and this becomes schizonts then merozoites and later trophozoites.

 

 

 

Public health, Prevention strategies and Vaccines

 

  1. Mosquito bed nets
  2. Medication – Mefloquine, Chlorquine,
  3. Vector control
  4. Residual spraying using insecticides

 

 

Useful Web Links

 

  1. CDC: cdc.gov/malaria, http://www.cdc.gov/EID/content/14/11/1750.htm
  2. WHO: http://www.who.int/topics/malaria/en/

 

 

 

 

 

 

 

 

 

 

 

 

References –

 



[1] Chin W, Contacos PG, Coatney RG, Kimbal HR, 1965. Naturally acquired quotidian-    type malaria in man transferable to monkeys. Science 149:865.

 

[2] McCutchan TF, Piper RC, Makler MT, 2008. Use of Malaria Rapid Diagnostic Test to             Identify Plasmodium knowlesi Infection. Emerging Infectious Diseases 14:11

[3] Singh B,Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas    A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

[4] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium     knowlesi malaria after visiting Malaysian Borneo Malaria Journal 8:15.

 

[5] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas   A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[6] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas   A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[7] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas   A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[8] Haynes JD, Dalton JP, Klotz FW, McGinnis MH, Hadley TJ, Hudson DE, Miller LH, 1988. Receptor-like specificity of a Plasmodium knowlesi malarial protein that      binds to Duffy antigen ligands on erythrocytes. J Exp Med 167:1873

 

[9] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas   A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[10] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[11] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26.

 

[12] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium    knowlesi malaria after visiting Malaysian Borneo Malaria Journal 2009, 8:15.

 

[13] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium    knowlesi malaria after visiting Malaysian Borneo Malaria Journal 2009; 8:15.

 

[14] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium    knowlesi malaria after visiting Malaysian Borneo Malaria Journal 2009; 8:15.

 

[15] Singh B,Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas   A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[16] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium    knowlesi malaria after visiting Malaysian Borneo Malaria Journal: 8:15,2009.

 

[17] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26.

 

[18] Haynes JD, Dalton JP, Klotz FW, McGinnis MH, Hadley TJ, Hudson DE, Miller LH:            Receptor-like specificity of a Plasmodium knowlesi malarial protein that binds to Duffy antigen ligands on erythrocytes. J Exp Med 167:1873, 1988

 

[19] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26.

 

[20] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26

 

[21] Bronner U, Divis PCS, Frnert  A, Singh B, 2009. Swedish traveller with Plasmodium    knowlesi malaria after visiting Malaysian Borneo Malaria Journal 2009; 8:15.

 

[22] Singh B, Sung LK, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi     infections in human beings. The Lancet 363:1006

 

[23] Cox-Singh J, Davis TME, Lee KS, Shamsul SSG, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B, 2008. Plasmodium knowlesi Malaria in Humans Is Widely   Distributed and Potentially Life Threatening. CID 2008:46.

 

 

[24] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26

 

[25] Ng OT, Ooi EE, Lee CC, Lee PJ, Ng LC, Wong PS Ming Tu TM, Loh JP, Leo YS,        2008. Naturally Acquired Human Plasmodium knowlesi Infection, Singapore.        Emerging Infectious Diseases, 2008; 14:5.

 

[26] Vythilingam I, NoorAzian YM, Huat TC, Jiram AI,Yusri YM, Azahari AH, NorParina I, NoorRain A, LokmanHakim S, 2008. Plasmodium knowlesi in humans,   macaques and mosquitoes in peninsular Malaysia. Parasit Vectors 2008; 1: 26.

 

[27] Cox-Singh J, Davis TME, Lee KS, Shamsul SSG, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B, 2008. Plasmodium knowlesi Malaria in Humans Is Widely   Distributed and Potentially Life Threatening. CID 2008:46.

 

[28]  Coggeshall LT, The Occurrence of Malaria Antiboides in Human Serum following         induced infection with plasmodium knowlesi. From the Laboratories of the            International Health Division of The Rockefeller Foundation;New York, 1940.

 

[29] Cox-Singh J, Davis TME, Lee KS, Shamsul SSG, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B, 2008. Plasmodium knowlesi Malaria in Humans Is Widely   Distributed and Potentially Life Threatening. CID 2008:46.

 

[30] Cox-Singh J, Davis TME, Lee KS, Shamsul SSG, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B, 2008. Plasmodium knowlesi Malaria in Humans Is Widely   Distributed and Potentially Life Threatening. CID 2008:46.