Plasmodium knowlesi-mediated zoonotic malaria: A challenge for elimination

Abstract

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.

INTRODUCTION

Malaria is caused by Plasmodium parasite, transmitted to humans by female Anopheles mosquitoes. The five causative agents that cause malaria are Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Of these, P. knowlesi with zoonotic implication is a major cause of malaria in South-East Asia.[1,2] Cases of P. knowlesi malaria have been reported from many countries of southern region of Asia including Malaysia, Indonesia, Thailand, Myanmar, Singapore, the Philippines, Brunei, Vietnam, and Cambodia.[3,4,5,6]

In 2017, as per the World Health Organization report, an estimated 219 million cases of malaria in 87 countries has been recorded with an estimated number of deaths of 435,000. Among the causative agents of malaria, P. falciparum accounted for 99.7% of estimated malaria cases in the WHO AFRO region, followed by South-East Asia (62.8%), Eastern Mediterranean (69%), and Western Pacific (71.9%). In WHO region of the Americas, 74.1% of malaria cases were due to P. vivax.[7] In a recent study conducted during 2015–2017, involving 3867 malaria cases, P. knowlesi accounted for 817 (80%), 677 (88%), and 2030 (98%) malaria cases in 2015, 2016, and 2017, respectively. There is a decrease in the number of malaria cases caused by P. falciparum which accounted for 110 (11%), 45 (6%), and 23 (1%), whereas P. vivax accounted for 61 (6%), 17 (2%), and 8 (0.4%) cases, respectively. Six malaria deaths related to P. knowlesi infection occurred in Sabah during this period.[8]

Malaria elimination depends on the interruption of transmission of species of Plasmodium in a geographic area. The emergence of zoonotic malaria caused by P. knowlesi is a challenge in elimination efforts, especially in Southeast Asia. The elimination of P. Knowlesi-mediated malaria threatens progress toward elimination and effectiveness of conventional methods of malaria control.[9]

ZOONOTIC IMPLICATION

People who stay overnight in forest area are at the risk of contracting zoonotic malaria from both human and nonhuman primate parasites. Among all species of malarial parasites, P. knowlesi is the most common cause in some parts of Malaysia. Cases of P. knowlesi malaria have been reported in other countries of Southeast Asia.[1] Identification of vector species and their study of biting behavior are important in disease control. It is now well established that P. knowlesi is an important cause of malaria in humans. It is the first significant species that causes zoonotic malaria. P. knowlesi is a parasite of macaques namely Macaca fascicularis, Macaca nemestrina, and Macaca leonina in southern part of Asia.

P. knowlesi parasitic infection leads to severe and often fatal disease in human beings.[10,11,12,13] P. knowlesi and P. cynomolgi are two species of parasite transmissible between humans and macaque through mosquito vectors. A study conducted in Laos reported that of the 276 samples tested, 64% were positive for Plasmodium species, with P. cynomolgi being the most common among long-tailed macaque population.[14] A study reported severe complicated P. knowlesi malaria in Thailand.[15] P. knowlesi infection is rare during pregnancy and if occurs, it may result in adverse maternal and pregnancy outcome.[16]

PATHOGENESIS AND IMMUNITY

P. knowlesi infection results vary from asymptomatic infection to severe and fatal disease with high parasitemia. P. knowlesi infects both human and nonhuman primates, and the erythrocytic cycle of schizogony is associated with the development of clinical signs and symptoms. The parasite takes about 24 h to complete cycle rather than 48–72 h in other species of malarial parasite.[17,18]

Anopheles dirus and Anopheles crascens are excellent vectors of P. knowlesi. It is reported that a single bite of infected mosquito is sufficient to infect a monkey with P. knowlesi.[19] P. knowlesi-infected erythrocytes from humans can bind specifically in variable manner to endothelial receptors (intercellular adhesion molecule-1 and vascular cell adhesion molecule).[20] It is observed that the level of monocyte chemoattractant protein-1, macrophage inflammatory protein-1 β, interleukin-8, and tumor necrosis factor alpha increased in complicated cases of P. knowlesi infection and decreased in complicated P. falciparum malaria.[21]

The severity in malaria and host immune evasion much depends on antigenic variation that is exhibited at parasite-infected red blood cell surface.[22] Anti-inflammatory responses were common in the primary infection of P. knowlesi. Repeat infection included expression of tumor necrosis factor-alpha and host-destructive effects. The simian malaria or rhesus monkey model is well suited to study the regulation of immunity to acute infection caused by parasite.[23] The role played by immune complexes in the evasion of P. knowlesi from destruction by macrophages was studied in vitro using whole antigen and soluble antigen with muramyl dipeptide (MDP) being an adjuvant. This MDP preparation afforded some protection to the test animals.[24] Earlier study findings indicate that in P. knowlesi infection in rhesus monkeys, immune complexes may inhibit the binding of parasitized erythrocytes with mononuclear phagocytes to overcome host defense mechanisms.[25] In another study, clinical immunity was demonstrated in four of the six immunized rhesus monkeys when challenged at a time of known or presumed high inhibitory antibody titer. The failure in immunization was attributed to the insufficient level of specific antibody.[26]

The surface antigen of P. knowlesi sporozoites namely circumsporozite (CS protein) is thought to be important in eliciting protective immunity in humans. The homology of two regions of amino acids in circumsporozite proteins of both P. knowlesi and P. falciparum parasites, with the conserved sequences, can form the basis for an effective vaccine. It is possible to produce an immunogen for such a candidate vaccine.[27] In one of the important studies, it was observed that, when immunized with partially purified preparation of P. knowlesi gametes, transmission blocking immunity persisted at high level in most of the rhesus monkeys. Further, immunity to other stages of parasites such as sporozoites and erythrocytic asexual forms failed to induce immunity against parasite gametes.[28]

TREATMENT

P. knowlesi parasites are highly sensitive to artemisinins. They are moderately sensitive to chloroquine and less sensitive to mefloquine.[29]

Intravenous artesunate is highly effective in severe P. knowlesi malaria and also in cases with moderately high parasitaemia but otherwise uncomplicated malaria.[30]

A study reported that while observing remarkable achievements in eliminating malaria in China, despite increases in imported cases, efforts are needed to reinforce the management of imported cases and the treatment of complicated malaria.[31] Although there is an increase in P. knowlesi malaria cases, the notification of fatality rate decreased, likely because of using intravenous artesunate for treatment.[32] The deaths in P. knowlesi malaria can be prevented with earlier presentation, timely diagnosis, and administration of intravenous artesunate.[33]

CONTROL OF PLASMODIUM KNOWLESI MALARIA

In recent years, molecular methods are used in the detection of parasite.[34] Molecular methods such as polymerase chain reaction and microscopy are frequently used in the identification of species of Plasmodium. With decreased prevalence of other species of Plasmodium, molecular surveillance is required in countries that are affected by P. knowlesi malaria. Molecular methods are also useful in the identification of P. knowlesi in travelers and migrants.[35] A study recommended the development of rapid detection test in diagnosing P. knowlesi infections in rural health-care services.[3] Two divergent parasite subpopulations were reported in humans by genotyping of the parasite.[36] Further studies are required to identify environmental and social risk factors and incorporate intervention measures to prevent infection by P. knowlesi. Studies indicated the association of P. knowlesi infection with sociodemographic, occupational, transmission, as well as geographical factors.[35,37,38,39]

The parasite infection not only can result in high parasitaemia but also severe and fatal malaria in humans. Thus, it necessitates requirement of urgent control measures.

A major surface protein (MSP4) of the merozoite induces a strong antibody response, thus resulting decrease in malaria morbidity. The MSP4 is a potential vaccine candidate. A study genetically characterized the full-length msp4 gene from clinical isolates of P. knowlesi from Malaysia.[40] Merozoite surface protein 119 (MSP-119) is also a potential candidate for vaccine that provides protective immunity against asexual-stage parasite and appears to be a leading immunogenic antigen.[41] In one of the studies, the sensitivity of purified pkMSP-119 toward the detection of P. knowlesi infection was with a specificity of 86%.[42]

The risk of P. knowlesi infection to tourists and visitors to endemic area can be minimized by using prophylactic measures such as application of mosquito/insect repellants and use of repellant impregnated uniforms and bed nets in jungle camp sites.[6]

P. knowlesi, like other species, can be transmitted through infected blood transfusion. A study[43] on blood transfusion-transmitted malaria reported that such transmissions can occur. This study consisted of hundred cases of Plasmodium species detected during blood transfusion, of which two were of P. knowlesi parasite.

CONCLUSION

The main opportunities to control and eliminate zoonotic malaria are the availability of molecular tests for accurate diagnosis and identification of vectors and national programs to control malaria transmitted from person to person. The zoonotic malaria is definitely a threat in the elimination and subsequent eradication of all types of malaria from this globe.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.