Plasmodium malariae

Malaria has been recognized since the Greek and Roman civilizations over 2,000 years ago, with different patterns of fever described by the early Greeks.[2] In 1880, Alphonse Laveran discovered that the causative agent of malaria is a parasite.[2] Detailed work of Golgi in 1886 demonstrated that in some patients there was a relationship between the 72-hour life cycle of the parasite and the chill and fever patterns in the patient.[2] The same observation was found for parasites with 48-hour cycles.[2] Golgi concluded that there must be more than one species of malaria parasite responsible for these different patterns of infection.[2]

Relative incidence of Plasmodium species by country of origin for imported cases to non-endemic countries, showing P. malariae in yellow.[3]

Each year, approximately 500 million people will be infected with malaria worldwide[4] Of those infected, roughly two million will die from the disease.[5] Malaria is caused by six Plasmodium species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, Plasmodium malariae and Plasmodium knowlesi.[2] At any one time, an estimated 300 million people are said to be infected with at least one of these Plasmodium species and so there is a great need for the development of effective treatments for decreasing the yearly mortality and morbidity rates.[6]

Geographical areas of malaria transmission

P. malariae is the one of the least studied of the six species that infect humans, in part because of its low prevalence and milder clinical manifestations compared to the other species. It is widespread throughout sub-Saharan Africa, much of southeast Asia, Indonesia, on many of the islands of the western Pacific and in areas of the Amazon Basin of South America.[5] In endemic regions, prevalence ranges from less than 4% to more than 20%,[7] but there is evidence that P. malariae infections are vastly underreported.[8]

The Centers for Disease Control (CDC) has an application that allows people to view specific parts of the world and how they are affected by Plasmodium vivax, and other types of the Plasmodium parasite. It can be found at the following link: http://cdc.gov/malaria/map/index.html.

P. malariae can infect several species of mosquito and can cause malaria in humans.[2] P. malariae can be maintained at very low infection rates among a sparse and mobile population because unlike the other Plasmodium parasites, it can remain in a human host for an extended period of time and still remain infectious to mosquitoes.[8]

P. vivax and P. ovale sitting in EDTA for more than 30 minutes before the blood film is made will look very similar in appearance to P. malariae, which is an important reason to warn the laboratory immediately when the blood sample is drawn so they can process the sample as soon as it arrives.

Microscopically, the parasitised red blood cell (erythrocyte) is never enlarged and may even appear smaller than that of normal red blood cells. The cytoplasm is not decolorized and no dots are visible on the cell surface. The food vacuole is small and the parasite is compact. Cells seldom host more than one parasite. Band forms, where the parasite forms a thick band across the width of the infected cell, are characteristic of this species (and some would say is diagnostic). Large grains of malarial pigment are often seen in these parasites: more so than any other Plasmodium species, 8 merozoites.

Failure to detect some P. malariae infections has led to modifications of the species-specific primers and to efforts towards the development of real-time PCR assays.[2] The development of such an assay has included the use of generic primers that target a highly conserved region of the 18S rRNA genes of the four human-infecting species of Plasmodium.[2] This assay was found to be highly specific and sensitive. Although serologic tests are not specific enough for diagnostic purposes, they can be used as basic epidemiologic tools.[2] The immunofluorescent-antibody (IFA) technique can be used to measure the presence of antibodies to P. malariae..[2] A pattern has emerged in which an infection of short duration causes a rapidly declining immune response, but upon re-infection or recrudescence, the IFA level rises significantly and remains present for many months or years.[5]

The increasing need to correctly identify P. malariae infection is underscored by its possible anti-malarial resistance. In a study by Müller-Stöver et al., the researchers presented three patients who were found to be infected with the parasite after taking anti-malarial medications.[13] Given the slower pre-erythrocytic development and longer incubation period compared to the other malaria causing Plasmodium species, the researchers hypothesized that the anti-malarials may not be effective enough against the pre-erythrocytic stages of P. malariae.[13] They thought that further development of P. malariae can occur when plasma concentrations of the anti-malarials gradually decrease after the anti-malarial medications are taken. According to Dr. William E. Collins from the Center of Disease Control (CDC), chloroquine is most commonly used for treatment and no evidence of resistance to this drug has been found.[14] In that event, it is possible that the results from Müller-Stöver et al. provided isolated incidences.

The food vacuole is the specialized compartment that degrades hemoglobin during the asexual erythrocytic stage of the parasite.[6] It is implied that effective drug treatments can be developed by targeting the proteolytic enzymes of the food vacuole. In a paper published in 1997, Westling et al.[5] focused their attention on the aspartic endopeptidase class of enzymes, simply called plasmepsins. They sought to characterize the specificity for the enzymes cloned from P. vivax and P. malariae. Using substrate specificity studies and inhibitor analysis, it was found that the plasmepsins for P. malariae and P. vivax showed less specificity than that for P. falciparum. Unfortunately, this means that the development of a selective inhibitor for P. malariae may prove more challenging than the development of one for P. falciparum.[5] Another study by Bruce et al.[7] presented evidence that there may be regular genetic exchange within P. malariae populations. Six polymorphic genetic markers from P. malariae were isolated and analyzed in 70 samples of naturally acquired P. malariae infections from different parts of the world. The data showed a high level of multi-genotypic carriage in humans.[7]

Both of these experiments illustrate that development of vaccine options will prove challenging, if not impossible. Dr. William Collins doubts that anyone is currently looking for possible vaccines for P. malariae[14] and given the complexity of the parasite it can be inferred why. He states that very few studies are conducted with this parasite,[14] perhaps as a result of its perceived low morbidity and prevalence. Collins cites the great restrictions of studies with chimpanzees and monkeys as a sizeable barrier.[14] Since the Plasmodium brasilianium parasite that infects South American monkeys is thought to be an adapted form of P. malariae, more research with P. brasilianium may hold valuable insight into P. malariae.

A recent study shows that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. Thus, a lack of host specificity in mammalian hosts can be hypothesized and quartan malaria can be considered to be a true anthropozoonosis [15]

The continuing work with the plasmepsin associated with P. malariae, plasmepsin 4, by Professor Ben Dunn and his research team from the University of Florida may provide hope for long term malaria control in the near future.[16]

In 2017 the full genome was published.[17] The sequences can be accessed on geneDB.org and plasmoDB.org.

• List of parasites (human)
• Malaria
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium ovale