View source for Plasmodium malariae

{{Short description|Species of single-celled organism}}
{{Use dmy dates|date=April 2020}}
{{Speciesbox
| image = Mature Plasmodium malariae schizont PHIL 2715 lores.jpg
| image_caption = [[Giemsa]]-stained micrograph of a mature ''Plasmodium malariae'' [[wikt:schizont|schizont]]
| genus = Plasmodium
| species = malariae
| authority = ([[Raimondo Feletti|Feletti]] &amp; [[Giovanni Battista Grassi|Grassi]], 1889)
| synonyms =
* ''Haemamoeba malariae'' <small>Feletti and Grassi, 1889</small>
* ''Plasmodium malariae'' var. ''quartanae'' <small>Celli and Sanfelice, 1891</small>
* ''Plasmodium malariae quartanae'' <small>Kruse, 1892</small>
* ''Haemamoeba laverani'' var. ''quartanae'' <small>Labbe, 1894</small>
* ''Plasmodium rodhaini'' <small>Brumpt, 1939</small>
| synonyms_ref = <ref>{{cite book|vauthors=Coatney GR, Collins WE, Warren M, Contacos PG |year=1971|title=The primate malarias|publisher=Division of Parasitic Disease, CDC|chapter=18 ''Plasmodium malariae'' (Grassi and Feletti, 1890)|pages=209|chapter-url=http://stacks.cdc.gov/view/cdc/6538}}</ref>
}}

'''''Plasmodium malariae''''' is a parasitic [[protozoan]] that causes malaria in humans.  It is one of several species of ''Plasmodium'' [[parasite]]s that infect other organisms as pathogens, also including ''[[Plasmodium falciparum]]'' and ''[[Plasmodium vivax]]'', responsible for most [[malaria]]l infection.  Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by ''P. falciparum'' or ''P. vivax''. The signs include [[fever]]s that recur at approximately three-day intervals – a ''[[quartan fever]]'' or ''quartan malaria'' – longer than the two-day (tertian) intervals of the other malarial parasite.

==History==
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.<ref name=Collins>{{cite journal | vauthors = Collins WE, Jeffery GM | title = Plasmodium malariae: parasite and disease | journal = Clinical Microbiology Reviews | volume = 20 | issue = 4 | pages = 579–92 | date = October 2007 | pmid = 17934075 | pmc = 2176047 | doi = 10.1128/CMR.00027-07 }}</ref> In 1880, [[Alphonse Laveran]] discovered that the causative agent of malaria is a parasite.<ref name=Collins/> Detailed work of [[Camillo Golgi|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.<ref name=Collins/> The same observation was found for parasites with 48-hour cycles.<ref name=Collins/> Golgi concluded that there must be more than one species of malaria parasite responsible for these different patterns of infection.<ref name=Collins/>

==Epidemiology==
[[File:Relative incidence of Plasmodium (malaria) species by country of origin for imported cases to non-endemic countries.png|thumb|left|Relative incidence of Plasmodium species by country of origin for imported cases to non-endemic countries, showing ''P. malariae'' in yellow.<ref name="Tatem2017">{{cite journal| author=Tatem AJ, Jia P, Ordanovich D, Falkner M, Huang Z, Howes R | display-authors=etal| title=The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics. | journal=Lancet Infect Dis | year= 2017 | volume= 17 | issue= 1 | pages= 98–107 | pmid=27777030 | doi=10.1016/S1473-3099(16)30326-7 | pmc=5392593 }}</ref>]]
Each year, approximately 500 million people will be infected with malaria worldwide.<ref name=Madabushi>{{cite journal | vauthors = Madabushi A, Chakraborty S, Fisher SZ, Clemente JC, Yowell C, Agbandje-McKenna M, Dame JB, Dunn BM, McKenna R | title = Crystallization and preliminary X-ray analysis of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae | journal = Acta Crystallographica Section F | volume = 61 | issue = Pt 2 | pages = 228–31 | date = February 2005 | pmid = 16511002 | pmc = 1952262 | doi = 10.1107/S1744309105001405 }}</ref> Of those infected, roughly two million will die from the disease.<ref name=Westling>{{cite journal | vauthors = Westling J, Yowell CA, Majer P, Erickson JW, Dame JB, Dunn BM | title = Plasmodium falciparum, P. vivax, and P. malariae: a comparison of the active site properties of plasmepsins cloned and expressed from three different species of the malaria parasite | journal = Experimental Parasitology | volume = 87 | issue = 3 | pages = 185–93 | date = November 1997 | pmid = 9371083 | doi = 10.1006/expr.1997.4225 }}</ref> Malaria is caused by six ''[[Plasmodium]]'' species: ''[[Plasmodium falciparum]]'', ''[[Plasmodium vivax]],'' ''[[Plasmodium ovale curtisi]]'', ''[[Plasmodium ovale wallikeri]]'', ''Plasmodium malariae'' and ''[[Plasmodium knowlesi]]''.<ref name=Collins/> 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.<ref name=Clemente>{{cite journal | vauthors = Clemente JC, Govindasamy L, Madabushi A, Fisher SZ, Moose RE, Yowell CA, Hidaka K, Kimura T, Hayashi Y, Kiso Y, Agbandje-McKenna M, Dame JB, Dunn BM, McKenna R | title = Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor | journal = Acta Crystallographica Section D | volume = 62 | issue = Pt 3 | pages = 246–52 | date = March 2006 | pmid = 16510971 | doi = 10.1107/S0907444905041260 | bibcode = 2006AcCrD..62..246C }}</ref>
[[File:Geographical areas of malaria transmission 2014.png|thumb|Geographical areas of malaria transmission]]

''P. malariae'' is 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.<ref name=Westling/> In endemic regions, prevalence ranges from less than 4% to more than 20%,<ref name=Bruce>{{cite journal | vauthors = Bruce MC, Macheso A, Galinski MR, Barnwell JW | title = Characterization and application of multiple genetic markers for Plasmodium malariae | journal = Parasitology | volume = 134 | issue = Pt 5 | pages = 637–50 | date = May 2007 | pmid = 17140466 | pmc = 1868962 | doi = 10.1017/S0031182006001958 }}</ref> but there is evidence that ''P. malariae'' infections are vastly underreported.<ref name=Mohapatra>{{cite journal | vauthors = Mohapatra PK, Prakash A, Bhattacharyya DR, Goswami BK, Ahmed A, Sarmah B, Mahanta J | title = Detection & molecular confirmation of a focus of Plasmodium malariae in Arunachal Pradesh, India | journal = The Indian Journal of Medical Research | volume = 128 | issue = 1 | pages = 52–6 | date = July 2008 | pmid = 18820359 }}</ref>

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.

==Role in disease==
''P. malariae'' can infect several species of mosquito and can cause malaria in humans.<ref name=Collins/> ''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.<ref name=Mohapatra/>

===Vector===
The vector of transmission of the parasite is the female ''[[Anopheles]]'' mosquito, but many different species have been shown to transmit the parasite at least experimentally.<ref name=Collins/> Collins and Jeffrey report over thirty different species, which vary by geographic region.<ref name=Collins/>

===Incubation period===
Information about the [[prepatent period]], or the period of time between the infection of the parasite and demonstration of that parasite within the body, of ''P. malariae'' associated malaria is limited, but the data suggests that there is great variation, often the length of time depending on the strain of ''P. malariae'' parasite.<ref name=Collins/> Usually, the prepatent period ranges from 16 to 59 days.<ref name=Collins/>

===Infection in humans===
''Plasmodium malariae'' causes a chronic infection that in some cases can last a lifetime. The ''P. malariae'' parasite has several differences between it and the other ''Plasmodium'' parasites, one being that maximum parasite counts are usually low compared to those in patients infected with ''P. falciparum'' or ''P. vivax.''<ref name=Collins/> The reason for this can possibly be accounted for by the lower number of merozoites produced per [[erythrocytic cycle]], the longer 72-hour developmental cycle (compared to the 48-hour cycle of ''P. vivax'' and ''P. falciparum''), the preference for development in older erythrocytes and the resulting earlier development of immunity by the human host.<ref name=Collins/>
Another defining feature of ''P. malariae'' is that the fever manifestations of the parasite are more moderate relative to those of ''P. falciparum'' and ''P. vivax'' and fevers show quartan periodicity.<ref name=Bruce/> Along with bouts of fever and more general clinical symptoms such as chills and nausea, '''the presence of edema and the nephrotic syndrome''' has been documented with some ''P. malariae'' infections.<ref name=Collins/> It has been suggested that immune complexes may cause structural glomerular damage and that renal disease may also occur.<ref name=Collins/> Although ''P. malariae'' alone has a low morbidity rate, it does contribute to the total morbidity caused by all ''Plasmodium'' species, as manifested in the incidences of anemia, low birth rate and reduced resistance to other infections.<ref name=Bruce/>

Due to a similarity in the appearances of the pathogens, ''P. knowlesi'' infections are often misdiagnosed as ''P. malariae'' infections. Molecular analysis is usually required for an accurate diagnosis.<ref name=Singh2004>{{cite journal | vauthors = Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, Thomas A, Conway DJ | title = A large focus of naturally acquired Plasmodium knowlesi infections in human beings | journal = Lancet | volume = 363 | issue = 9414 | pages = 1017–24 | date = March 2004 | pmid = 15051281 | doi = 10.1016/S0140-6736(04)15836-4 | s2cid = 7776536 | url = http://ir.unimas.my/2202/1/A%20large%20focus%20of%20naturally%20acquired%20Plasmodium%20knowlesi%20infections%20in%20human%20beings.pdf }}</ref>

===Diagnostics===
The preferable method for diagnosis of ''P. malariae'' is through the examination of peripheral blood films stained with Giemsa stain.<ref name=Collins/> PCR techniques are also commonly used for diagnoses confirmation as well as to separate mixed ''Plasmodium'' infections.<ref name=Collins/> Even with these techniques, however, it may still be impossible to differentiate infections, as is the case in areas of South America where humans and monkeys coexist and ''P. malariae'' and ''P. brasilianum'' are not easily distinguishable.<ref name=Collins/>

==Biology==
[[File:Plasmodium.png|right|thumb|200px|As a protist, ''Plasmodium'' is a eukaryote of the phylum Apicomplexa. Unusual characteristics of this organism in comparison to general eukaryotes include the rhoptry, micronemes, and polar rings near the apical end. ''Plasmodium'' is known best for the infection it causes in humans, namely, malaria.]]

===Life cycle===
[[File:Falciparum-life-cycle-final.jpg|thumb|Plasmodium malariae wiki]]
''P. malariae'' is the only human malaria parasite that causes [[fever]]s which recur at approximately three-day intervals (therefore occurring every fourth day, a ''quartan fever''), longer than the two-day (''tertian'') intervals of the other malarial parasites.<ref name="cdc">{{cite web| title =Biology: Malaria (CDC malaria)| url =https://www.cdc.gov/malaria/biology/parasites/index.htm| url-status =dead| archive-url =https://web.archive.org/web/20081013123447/http://www.cdc.gov/Malaria/biology/parasites/index.htm| archive-date =13 October 2008}}</ref>

===Human infection===

====Liver stage and blood stage====

In the liver stage, many thousands of merozoites are produced in each schizont.<ref name=Collins/> As the merozoites are released, they invade erythrocytes and initiate the erythrocytic cycle, where the parasite digests hemoglobin to obtain amino acids for protein synthesis.<ref name=Westling/>

The total length of the intraerythrocytic development is roughly 72 hours for ''P. malariae''.<ref name="1.5">{{cite web  | title = Malaria eModule - ASEXUAL ERYTHROCYTIC STAGES  | url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5.html  | access-date = 11 December 2007  | archive-date = 22 December 2007  | archive-url = https://web.archive.org/web/20071222163324/http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5.html  | url-status = dead  }}</ref>

At the schizont stage, after [[schizogonic division]], there are roughly 6–8 parasite cells in the erythrocyte.<ref name="1.5"/>

Following the erythrocytic cycle, which lasts for seventy two hours on average, six to fourteen merozoites are released to reinvade other erythrocytes.<ref name=Collins/> Finally, some of the merozoites develop into either micro- or macrogametocytes.<ref name=Collins/> The two types of gametocytes are taken into the mosquito during feeding and the cycle is repeated.<ref name=Collins/> There are no animal reservoirs for ''P. malariae.''

====Mosquito stage====
Similar to the other human-infecting ''Plasmodium'' parasites, ''Plasmodium malariae'' has distinct developmental cycles in the ''Anopheles'' mosquito and in the human host.<ref name=Collins/> The mosquito serves as the definitive host and the human host is the intermediate.<ref name=Collins/> When the ''Anopheles'' mosquito takes a blood meal from an infected individual, gametocytes are ingested from the infected person.<ref name=Collins/> A process known as [[exflagellation]] of the [[microgametocyte]] soon ensues and up to eight mobile [[microgamete]]s are formed.<ref name=Collins/>

====Sexual stage====
Following fertilization of the [[macrogamete]], a mobile ookinete is formed, which penetrates the peritropic membrane surrounding the blood meal and travels to the outer wall of the mid-gut of the mosquito.<ref name=Collins/> The oocyst then develops under the basal membrane and after a period of two to three weeks a variable amount of sporozoites are produced within each oocyst.<ref name=Collins/> The number of sporozoites that are produced varies with temperature and can range from anywhere between many hundreds to a few thousand.<ref name=Collins/>
Eventually, the oocyst ruptures and the sporozoites are released into the hemocoel of the mosquito. The sporozoites are then carried by the circulation of the hemolymph to the salivary glands, where they become concentrated in the acinal cells.<ref name=Collins/> A small number of sporozoites are introduced into the salivary duct and injected into the skin of the bitten human.<ref>{{cite journal |last1=Ménard |first1=R |last2=Tavares |first2=J |last3=Cockburn |first3=I |last4=Markus |first4=M |last5=Zavala |first5=F |last6=Amino |first6=R |title=Looking under the skin: the first steps in malarial infection and immunity |journal=Nature Reviews Microbiology |date=2013 |volume=11 |issue=10 |pages=701–712 |doi=10.1038/nrmicro3111 |pmid=24037451|s2cid=21437365 |doi-access=free }}</ref> This subsequently leads to the cycle in the human liver.<ref name=Collins/>

===Morphology===
The ring stages that are formed by the invasion of [[merozoite]]s released by rupturing liver stage [[schizont]]s are the first stages that appear in the blood.<ref name=Collins/> The ring stages grow slowly but soon fill one-fourth to one-third of the parasitized cell.<ref name=Collins/> Pigment increases rapidly and the half-grown parasite may have from 30 to 50 jet-black granules.<ref name=Collins/> The parasite changes various shapes as it grows and stretches across the host cell to form the band form.<ref name=Collins/>

==Laboratory considerations==
''[[Plasmodium vivax|P. vivax]]'' and ''[[Plasmodium ovale|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.

==Management and therapy==
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]].<ref name=Collins/> 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''.<ref name=Collins/> 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.<ref name=Collins/> The immunofluorescent-antibody (IFA) technique can be used to measure the presence of antibodies to ''P. malariae.''.<ref name=Collins/> 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.<ref name=Westling/>

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.<ref name=Muller-Stover>{{cite journal | vauthors = Müller-Stöver I, Verweij JJ, Hoppenheit B, Göbels K, Häussinger D, Richter J | title = Plasmodium malariae infection in spite of previous anti-malarial medication | journal = Parasitology Research | volume = 102 | issue = 3 | pages = 547–50 | date = February 2008 | pmid = 18060428 | doi = 10.1007/s00436-007-0804-4 | s2cid = 12491253 }}</ref> 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.''<ref name=Muller-Stover/> 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.<ref name=mCollins>Collins, William. "RE: Current research on ''Plasmodium malariae.''" Email to Chibuzo Eke. 18 February 2009.</ref> In that event, it is possible that the results from Müller-Stöver ''et al.'' provided isolated incidences.

==Public health, prevention strategies and vaccines==
The food vacuole is the specialized compartment that degrades hemoglobin during the asexual erythrocytic stage of the parasite.<ref name=Clemente/> 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.''<ref name=Westling/> 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.''<ref name=Westling/>
Another study by Bruce ''et al.''<ref name=Bruce/> 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.<ref name=Bruce/>

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''<ref name=mCollins/> and given the complexity of the parasite it can be inferred why. He states that very few studies are conducted with this parasite,<ref name=mCollins/> 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.<ref name=mCollins/> 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.<ref>{{citation|surname1=Albert Lalremruata, Magda Magris, Sarai Vivas-Martínez, Maike Koehler, Meral Esen|periodical=eBioMedicine|title=Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon|volume=2|issue=9|at=pp.&nbsp;1186–1192|date=September 2015|doi=10.1016/j.ebiom.2015.07.033
|pmid=26501116|pmc=4588399|doi-access=free}}</ref>

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.<ref>Dunn, Ben."RE:Current research on ''Plasmodium malariae.''" Email to Chibuzo Eke. 18 February 2009.</ref>

==Genome==
In 2017 the full genome was published.<ref name=Rutledge2017>{{cite journal | vauthors = Rutledge GG, Böhme U, Sanders M, Reid AJ, Cotton JA, Maiga-Ascofare O, Djimdé AA, Apinjoh TO, Amenga-Etego L, Manske M, Barnwell JW, Renaud F, Ollomo B, Prugnolle F, Anstey NM, Auburn S, Price RN, McCarthy JS, Kwiatkowski DP, Newbold CI, Berriman M, Otto TD | title = Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution | journal = Nature | volume = 542 | issue = 7639 | pages = 101–104 | date = February 2017 | pmid = 28117441 | pmc = 5326575 | doi = 10.1038/nature21038 | bibcode = 2017Natur.542..101R }}</ref> The sequences can be accessed on [http://www.genedb.org/Homepage/Pmalariae geneDB.org ] and [http://plasmodb.org/ plasmoDB.org].

== See also ==
* [[List of parasites (human)]]
* [[Malaria]]
* [[Plasmodium falciparum]]
* [[Plasmodium vivax]]
* [[Plasmodium ovale]]

== References ==
{{Scholia|topic}}
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{{Alveolata}}
{{Malaria}}
{{Chromalveolate diseases}}
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{{DEFAULTSORT:Plasmodium Malariae}}
[[Category:Plasmodium|malariae]]