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CLINICAL MICROBIOLOGY REVIEWS, Oct. 2007, p. 579–592 0893-8512/07/$08.00ϩ0 doi:10.1128/CMR.

00027-07 Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Vol. 20, No. 4

Plasmodium malariae: Parasite and Disease
William E. Collins* and Geoffrey M. Jeffery
Centers for Disease Control and Prevention, National Center for Zoonotic, Vector Borne and Enteric Diseases, Division of Parasitic Diseases, Chamblee, Georgia 30341, and U.S. Public Health Service, Atlanta, Georgia INTRODUCTION .......................................................................................................................................................579 LIFE HISTORY ..........................................................................................................................................................579 Human Host ............................................................................................................................................................581 Prepatent period .................................................................................................................................................581 Fever .....................................................................................................................................................................581 Parasitemia ..........................................................................................................................................................581 Recrudescence .....................................................................................................................................................582 Preerythrocytic Stages............................................................................................................................................582 Mosquito Host.........................................................................................................................................................583 DISTRIBUTION .........................................................................................................................................................583 LABORATORY DIAGNOSIS....................................................................................................................................584 Preservation .............................................................................................................................................................586 SEROLOGIC STUDIES ............................................................................................................................................586 MOLECULAR STUDIES...........................................................................................................................................587 INFECTIONS IN CHIMPANZEES AND MONKEYS ..........................................................................................587 PATHOLOGY..............................................................................................................................................................588 ULTRASTRUCTURE .................................................................................................................................................589 RELATIONSHIP TO OTHER SPECIES ................................................................................................................589 REFERENCES ............................................................................................................................................................590 INTRODUCTION Plasmodium malariae is a malaria parasite that causes a disease that has been recognized since the Greek and Roman civilizations over 2,000 years ago. Quartan, tertian, and semitertian patterns of fever in patients were described by the early Greeks. After the discovery by Alphonse Laveran in 1880 (75) that the causative agent for malaria was a parasite, detailed studies on these organisms commenced. The early detailed work of Golgi in 1886 demonstrated that in some patients there was a relationship between the 72-hour life cycle of development of the parasites and a similar periodicity of the paroxysm (chill and fever pattern in the patient), whereas in other patients there were 48-hour cycles of development (54). He came to the conclusion that there must be more than one species of malaria parasite responsible for these different patterns of cyclical infection. Eventually, the different parasites were separated and given the names that they carry at the present time. In 1890, Grassi and Feletti (58) reviewed the available information and named P. malariae and P. vivax with the following statement: “C’est pour cela que nous distinguons, dans le genre Haemamoeba, trois espe `ces (H. malariae de la fie `vre quarte, H. vivax de la fie `vre tierce et H. praecox de la fie `vre quotidienne avec coutres intermittences etc.).” The current name for the parasite that we discuss here is Plasmodium malariae (Grassi and Feletti 1890). LIFE HISTORY Plasmodium malariae has developmental cycles in the mosquito and in the primate host (20). When gametocytes are ingested during mosquito feeding, a process called exflagellation of the microgametocyte occurs, resulting in the formation of up to eight mobile microgametes. 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 midgut of the Anopheles mosquito. There, under the basal membrane, the oocyst develops. After a period of 2 to 3 weeks, depending on the temperature, many hundreds to a few thousand sporozoites are produced within each oocyst. The oocyst ruptures and the sporozoites are released into the hemocoel of the mosquito. The sporozoites are carried by the circulation of the hemolymph to the salivary glands, where they become concentrated in the acinal cells. During feeding, a small number of sporozoites (Ͻ100) are introduced into the salivary duct and injected into the venules of the bitten human, to initiate the cycle in the liver. In the human, following introduction into the bloodstream, the sporozoites rapidly invade the liver within an hour, where, within a parenchymal cell, the parasite matures in approximately 15 days. Eventually many thousands of merozoites are produced in each schizont. Upon release, these merozoites invade erythrocytes and initiate the erythrocytic cycle. There is no evidence of quiescent liver stage forms (hypnozoites) such as are found in P. vivax and P. ovale infections in humans. However, not all liver stage forms will mature on the same day; biopsies indicate that these forms may rupture and release parasites over a number of days. Following a developmental
579

* Corresponding author. Mailing address: Centers for Disease Control and Prevention, National Center for Zoonotic, Vector Borne and Enteric Diseases, Division of Parasitic Diseases, Chamblee, GA 30341. Phone: (770) 488-4077. Fax: (770) 488-4253. E-mail: wec1@cdc.gov.

650 14.9 Maximum fever (oF) 102.0 106.350 4.100 11.0 106.0 103.240 4.6 106.976 3.0 105.080 6.4 104.8 106.0 106.725 7.620 2940 2. means are shown for the other parameters.4 105.6 105.0 105.750 8.460 6. TABLE 1.4 105.400 3.680 8.4 105.6 104.0 106. median.6 106.0 105.6 104.750 11.550 14.4 104.0 106.0 105.450 11.034 20.640 4.618 5.0 105.0 105.700 7.0 105.544 12.6 105.0 106.250 6.120 7.0 104.6 106.100 4.350 9.660 49.240 16.850 33.6 106.360 9.4 103.400 10.0 105.000 14.300 2. .850 12.160 17.4 105.920 34.0 105.0 105.608 13.108 5.320 29.434 5.648 2.4 105.0 105.4 104.0 106.840 8.776 14.2 Data are from reference 83.875 Days with parasitemia of Ͼ1.150 10.711 10.800 14.120 12.2 106.4 106.6 105.0 106.0 106. or meanb a b Days with parasitemia 517 94 134 63 119 107 114 130 263 84 170 100 61 65 120 132 73 98 67 102 81 66 272 65 65 167 127 79 71 72 88 62 76 85 77 72 96 163 78 92 76 67 60 65 112 69 160 726 101 62 111 120 78 78 76 69 64 63 132 85 93 60 77 72 74 92 74 218 68 60–726 Maximum parasitemia (/␮l) 1.0 106.000 2.100 6.330 12.8 105.350 6.450 8.5 Days with fever of Ն101°F 6 6 26 17 29 35 8 8 3 22 16 0 15 24 28 41 17 34 24 42 30 21 19 26 17 4 41 22 22 20 27 28 30 31 29 31 23 27 28 24 21 28 17 32 13 25 16 19 18 25 11 7 20 23 25 34 21 22 5 23 20 19 29 14 17 20 31 20 20 21.6 106.6 Days with fever of Ն104°F 0 1 9 13 14 1 0 0 1 21 1 0 5 21 12 5 7 19 20 16 19 17 4 15 4 0 20 20 21 9 14 17 8 24 17 15 10 10 8 21 17 15 4 9 2 11 9 7 0 12 3 5 8 18 4 17 5 18 1 4 13 12 21 12 5 7 16 7 1 10.208 3.2 106.4 104.6 103.4 105.2 106.2 105.4 106.0 104.2 105.0 106.850 8.6 106.350 3.0 105. Range and median are shown for days with parasitemia and maximum parasitemia.804 5. MICROBIOL.100 16.160 14. REV.950 6.580 COLLINS AND JEFFERY CLIN.4 105.413 8.000/␮l 14 9 22 23 53 34 40 8 11 48 9 25 15 51 55 82 26 66 53 87 63 44 85 52 38 21 93 57 49 46 64 49 70 66 57 59 30 61 54 66 59 51 41 48 71 36 90 75 72 48 36 20 55 48 64 53 42 47 101 70 55 51 59 28 55 34 59 62 49 50.880 11.2 106.6 105.4 106.350 6.0 105.950 5. Parasite counts and fever for 69 patients infected with Plasmodium malariae for 60 days or morea Patient G-0081 S-1037 S-1282 S-0619 S-1103 S-1007 S-1109 S-0623 S-1093 S-0398 S-1121 S-1112 G-0007 S-0489 S-1101 S-0647 S-1119 S-1061 S-1039 S-1090 S-1137 S-0408 S-0508 S-0488 S-0734 S-1120 S-0651 S-0960 S-0468 S-1068 S-1303 S-0532 S-0593 S-0788 S-1078 S-0495 G-0063 S-1042 S-0818 S-0396 S-1268 S-1105 G-0040 G-0013 S-1085 S-0984 S-1096 G-0080 G-0062 S-1071 G-0077 S-1041 S-0799 S-1151 G-0042 S-0600 S-0740 S-0752 S-1081 G-0026 S-0985 S-1072 S-0218 S-1289 G-0029 S-1015 G-0025 G-0110 G-0016 Range.6 105.875 9.6 105.650 10.752 10.100 16.6 103.850 15.8 105.600 12.240 3.6 106.

and 40-day prepatent periods. (123) in which they examined 420 paroxysms. vivax or P. It was estimated that perhaps 20% of patients in U. There are only a limited number of reports on the transmission of P.6oF. Plasmodium falciparum was less commonly used because of the difficulty of controlling infections with this species of parasite. The median maximum fever for the 69 patients was 105. as these data show. and Mer (86) transmitted a Palestinian strain to three patients.VOL.1°F (rectally). For these patients. P. Because fever regularly occurs again on the fourth day in many patients. malariae to patients. while others were not. Daily peak parasite counts and fever peaks in a patient infected with Plasmodium malariae. Prior to the introduction of penicillin for the treatment of syphilis. and infection with P.S. showing the synchronous quartan pattern of fever and peak parasite count. (83) with no known previous malaria infection who were allowed to have parasitemia of P. Parasitemia. malariae. It was believed that a combination of repeated episodes of high-intensity fever combined with a nonspecific stimulation of the immune system induced by the malaria parasite combined to destroy the spirochete. Ciuca et al. and Young and Burgess (120) reported prepatent periods of 29 and 59 days. Prepatent periods of 23 and 26 days were reported by de Buck (42) for four patients infected with a Vienna strain. falciparum or P. Boyd and Stratman-Thomas (10) reported prepatent periods of 27. and the prepatent periods were 33 and 36 days. the prepatent periods ranged from 24 to 33 days (40). The most detailed study of the paroxysm of P. malariae. Some fevers were introduced by chills. with the highest recorded being 106. malariae (16 to 59 days). 27 to 37 days) for American strains of P. The prepatent period is defined as the time until the first day that parasites are detected on a thick blood film. as shown in Fig. 1. in four additional patients the prepatent period ranged from 21 to 30 days (48). malariae is probably that by Young et al. in whom the periods were 26.100/␮l. It is also apparent that the fever occurred just prior to an increased parasite count associated with release of a new population of parasites. they were most often treated with P. on average. In transmission studies with a Nigerian strain involving four volunteers. for 72 h.4oF. 2007 PLASMODIUM MALARIAE: PARASITE AND DISEASE 581 FIG. and 31 days. Fever often occurred on an every-third-day pattern. malariae was standard practice in the treatment of the disease. Some of the merozoites develop into the two forms of gametocytes (micro.2 days (range. Lupascu et al. (ii) the extended 72-hour developmental cycle versus the 48-hour cycle of P. A retrospective examination of induced infections with P. vivax and P.9 and the median number of days of fever of Ն104oF was 10. Mackerras and Ercole (79) reported a 24-day period for a Melanesian strain. malariae to humans to determine prepatent periods. Thus. This is due to several factors: (i) the lower number of merozoites produced per erythrocytic cycle. 20. and Boyd and Stratman-Thomas (12) reported 28.and macrogametocytes). Young and Burgess (121) transmitted the USPHS strain of P.2. 8) merozoites are released to reinvade other erythrocytes. Maximum parasite counts are usually low compared to those in patients infected with P. Marotta and Sandicchi (81) reported incubation periods (days until symptoms first appeared) of 23 and 29 days in two patients. Human Host Prepatent period. (83). (78) reported incubation periods of 18 to 19 days for the VS strain. the cycle is repeated. Siddons (107) reported a prepatent period of 30 days. 32. One patient (S-1112) failed to exhibit fever of Ն101oF in spite of a maximum parasite count of 4. malaria was one of the most effective treatments for the disease (118). Fever. there is a wide range in the length in the prepatent period in mosquitotransmitted P. The average fever peak was 104. Shute and Maryon (104) reported the shortest prepatent period of 16 days for a West African strain. (iii) the preference of the parasite to developed in older erythrocytes. A listing of the days of fever of Ն101oF and Ն104oF and the maximum fevers for 69 of the patients examined by McKenzie et al. 1. the median number of days of fever of Ն101oF was 21. Boyd (9) reported on three different strains for which prepatent periods ranged from 28 to 37 days. falciparum. When they are taken into the mosquito during feeding. vivax (due to the Duffy negative blood grouping). and Kitchen (72) reported a mean prepatent period of 32. These data were extracted from the records of patients who were given malaria therapy for the treatment of neurosyphilis between 1940 and 1963. cycle in the erythrocyte that lasts. Fevers (Ն101oF) ranged in duration from 5 to 32 h. and 37 days for two different strains. mental hospitals had neurosyphilis (62). malariae was made by McKenzie et al. and (iv) the combination of . Because most African American patients were resistant to infection with P. malariae for 60 or more days is presented in Table 1. (18) reported prepatent periods for the Romanian VS strain ranging from 18 to 25 days. from 6 to 14 (average. with an average of 10 h 58 min. vivax. 28. malariae infections are often referred to as being “quartan” malaria.

malariae following infection with P. FIG. ovale (Table 4). no evidence of septum formation or plasmotomy. the maximum parasite count ranged from 1. The length of parasitemia was shorter. When the parasite counts for these patients were averaged for the first 40 days of patent parasitemia (Fig. 39 patients had been infected with P. 2. Lupascu et al. large clefts. The median maximum parasite count was 13. it was apparent that the parasite count peaked at approximately 2 weeks and then remained relatively stable. red-staining strands. Only one schizont was seen in Aotus hepatocytes at day 13. two or more nuclei were present. The maximum parasite counts ranged from 424/␮l to 19. either following donation of blood in which the recipient developed an infection or under stress. vivax (Table 3). The tissue stages of P. . for the life of the human host. malariae in China 50 years previously. 72-hour developmental cycle. and plaques in the mature schizonts. The median parasite count actually did not begin to decline until 60 days or more of patent parasitemia. Forty-six patients were infected following infection with P. Maximum parasite counts are limited in infections with P.000/␮l. REV. 10-.875/␮l (10. Millet et al. For example. In the 69 patients (Table 1). falciparum (Table 2). Schizonts were observed in chimpanzee hepatocytes at 8. often.582 COLLINS AND JEFFERY CLIN. malariae were first described by Bray (13. (83) had been infected with P. malariae in cultures of hepatocytes from chimpanzees and Aotus lemurinus griseimembra monkeys. Recrudescence. 14) in liver biopsy specimens from sporozoite-inoculated chimpanzees. and 13 days after inoculation of sporozoites.000/␮l.608/␮l. 9-. malariae following infection with P. Other patients in the data studied by McKenzie et al. (87) reported the development of preerythrocytic stages of P. whose infections have recrudesced after many years of dormancy. and 15 days after introduction of sporozoites of P. many peripheral and internal vacuoles.5 days with parasite counts of Ͼ1. The ratio between the number of days of fever of Ն101oF to Ն104oF was almost identical to that for patients with no previous infection.624/␮l. the blood stage parasites persist for extremely long periods. (116) report a case of an infection acquired in Greece over 40 years (and possibly up to 70 years) previous to splenectomy and subsequent diagnosis. malariae following previous infection with other species of malaria parasites.000/␮l. 2).250/␮l. these factors that allows for the earlier development of immunity by the human host.648/␮l to 49. 11-. it is believed. malariae. Collins et al. there were no pseudocytomeres. The schizonts were considered mature at 15 days. 14. The host cell nucleus was enlarged and pushed to one side. Some patients had long periods of parasitemia and extended periods when parasite counts were Ͼ1.25% of erythrocytes infected).575/␮l. The maximum parasite counts ranged from 312/␮l to 29. no cytomeres. it is believed that the parasites have persisted in the blood at very low densities. Vinetz et al. Preerythrocytic Stages The preerythrocytic tissue stages develop in the liver following the introduction of sporozoites. These patients averaged 50.825/␮l.000/␮l ϭ 0. malariae due to the low number of merozoites produced. and there were fewer days with parasite counts of Ͼ1.5-day-old forms. and preference for older erythrocytes. with the median being 6. 13. with a median count of 8. Plasmodium malariae does not relapse from persistent liver stage parasites. and no mature schizonts at these time points. (33) reported on a transfusion case in which the donor had probably acquired infection with P. MICROBIOL. and 12. Median parasite counts during the first 40 days of patent parasitemia for 69 patients infected with Plasmodium malariae. Because almost all of these longterm infections have been detected following transfusion donations. (77) obtained biopsy material from a chimpanzee at 12. 11. The main characteristics were enlargement of the host cell nucleus. 12-. Only eight patients were infected with P. However. with a median of 9. He was able to describe the 8-. In addition.680/␮l. There have been many reports of people who have left zones of endemicity and. The time required for maturation and release of merozoites from the mature schizonts to invasion of erythrocytes is approximately 15 days. The nuclei were always randomly distributed. In over 50% of the parasitized parenchymal cells.

270 3. In areas of endemicity in Africa. Mosquito Host Many different vectors have been shown to be capable.0 105.094 19.000/␮l Days with fever of Ն101°F Maximum fever (oF) Days with fever of Ն104°F S-1102 S-0679 S-1032 S-1333 S-1336 S-0403 S-0457 S-1295 S-1263 S-0937 S-0774 S-0678 S-1008 S-0463 S-1022 S-1321 S-0965 S-0782 S-0953 S-1313 S-0713 S-0791 S-1302 S-1018 S-1285 S-0995 S-0980 S-0760 S-1058 S-0775 S-1304 S-0991 S-1067 S-0778 S-0789 S-1065 S-1088 S-1002 S-0951 S-1050 S-0986 S-1338 S-0966 S-1079 S-0787 S-1004 Range.655 7. the first definitive studies were carried out by Shute and Maryon (105) on its development in Anopheles atroparvus mosquitoes.050 6. of infection with this parasite.0 106. Those that have been proven to be capable of transmitting P.8 105.591 6. These are listed in Table 5. 20. when incubated at a temperature of 25°C.4 105.210 8.2 105.4 102.472 14.625 6. falciparum infec- .0 105.4 104.722 8.080 4.6 106.4 106.0 105.0 106.520 6.6 105.800 13.8 105. DISTRIBUTION In general. with a mean of 38 ␮m.586 2. the mean oocyst diameter was 12 ␮m. at least experimentally.785 5.4 104.2 106. malariae coincides with that of P.0 105.8 105.2 104.910 4. The oocysts continued to grow so that by day 14 they ranged from 20 to 65 ␮m.0 106.350 1.608 0 0 0 0 6 5 7 20 43 30 17 35 8 18 79 12 21 20 52 30 77 41 56 30 21 27 41 75 12 24 38 28 51 55 22 39 28 42 10 35 41 46 10 36 44 26 29.250 29.6 106.0 105.335 5.VOL.4 106.3 Data are from reference 83.2 105.4 0 0 0 0 7 0 0 2 10 2 1 7 1 0 4 0 5 7 18 8 16 12 16 3 3 9 7 19 4 12 12 5 7 7 6 13 3 13 3 7 6 13 3 7 8 6 6.2 103.744 27.4 106. malariae in mosquitoes has been described by a number of workers.6 106. falciparum. with a range of 9 to 14 ␮m.550 11.350 1. Early differentiation and formation of sporozoites were apparent by day 14 (Fig.850 19.224 10.6 105.250 15. falciparuma Patient Days with parasitemia Maximum parasitemia (/␮l) Days with parasitemia of Ͼ1.8 105.4 104. The development of P.850 3.0 101.550 3.950 10.752 3.864 3.340 1.120 5.2 104.2 106.0 105.650 4.825 6.875 6.5 0 1 0 0 15 0 0 20 19 10 9 15 7 4 12 9 17 10 23 13 31 18 21 8 9 17 21 35 6 13 28 14 18 35 18 19 14 25 5 21 13 26 6 12 17 10 14.856 2.4 105.840 16. In the studies of Collins et al. the distribution of P. median. 2007 PLASMODIUM MALARIAE: PARASITE AND DISEASE 583 TABLE 2. 3). At day 6. Range and median are shown for days with parasitemia and maximum parasitemia.6 105. or meanb a b 47 199 120 52 72 192 195 477 206 90 74 76 87 58 128 33 68 40 73 42 129 57 74 39 141 47 96 97 20 34 55 94 78 66 30 51 41 57 24 85 50 62 19 46 70 42 20–477 312 430 540 580 1.6 105.6 105.4 105. Parasite counts and fever for 46 patients infected with Plasmodium malariae following previous infection with P. (38) with Anopheles freeborni.890 7.800 6.450 10.120 7.2 106.424 9.0 105. sporozoites were present in the salivary glands in 17 days. malariae to humans experimentally are also indicated.200 19. infections of P. malariae are mixed with P.8 104. means are shown for the other parameters.

6 105.0 106.960 5.300 3043 3.4 106. TABLE 3.0 106.420 13.521 9.2 105. As described by Coatney et al. Recently. in southeast Asia it has been shown that infections with the monkey malaria parasite Plasmodium knowlesi in humans have been misdiagnosed as being infections with P. along with Plasmodium brasilianum.840 2. Thus.0 104.0 106. It is also reported in areas of the Amazon Basin of South America.6 106.4 104. Range and median are shown for days with parasitemia and maximum parasitemia.700 6.040 9.4 106.0 106. brasilianum because they may.2 104.448 6. REV.0 106. inui may be transmitted to humans.0 105.4 105.6 105.050 13.0 106.250 0 0 0 5 11 10 32 33 22 15 14 55 49 25 64 17 47 25 22 39 44 51 49 18 48 29 11 47 37 14 18 21 24 32 15 34 36 33 18 27.160 2. The first stages that appear in the blood are the ring stages that are formed by the invasion of merozoites released by rupturing liver stage schizonts. median.624 9.6 106.0 107.2 106. much of southeast Asia.250 9.6 105. it is impossible to differentiate infections of P. PCR techniques are now routinely used in many laboratories to confirm diagnoses and to separate mixed infections.024 2.6 106.727 12. tions. 4) (20).8 106.4 105. malariae infections is unapparent unless PCR techniques are used to reveal low-level or subpatent infections.510 1.4 106. (Fig. knowlesi or P.250 4. vivaxa Patient Days with parasitemia Maximum parasitemia (/␮l) Days with parasitemia of Ͼ1. and on many of the islands of the western Pacific.350 13.750 14.0 105. malariae from infections of P.640 13. into Indonesia.0 105.8 106. be one and the same.6 106.8 106.150 12. or meanb a b 39 35 50 31 95 61 192 63 54 29 30 65 67 47 72 30 49 33 31 51 119 65 74 35 55 41 30 62 49 23 33 30 33 46 31 47 50 48 31 23–191 424 495 850 1.0 105.5 101.750 8.900 11.776 19.8 105.584 COLLINS AND JEFFERY CLIN. malariae infection is preferentially made by the examination of peripheral blood films stained with Giemsa stain.4 106.450 6.4 Data are from reference 83.000/␮l Days with fever of Ն101°F Maximum fever (oF) Days with fever of Ն104°F S-0749 S-0838 S-0325 S-0624 S-1267 S-0921 S-1283 S-0437 S-0874 S-0490 S-1082 S-0718 S-0866 S-1314 S-0518 S-0414 S-0586 S-0543 S-0916 S-0534 S-0592 S-0911 S-0504 S-0559 S-0560 S-0846 S-0790 S-0611 S-0571 S-0970 S-1019 S-0920 S-1046 S-0786 S-0675 S-1026 S-0610 S-0506 S-0939 Range. LABORATORY DIAGNOSIS Diagnosis of P. the presence of P. malariae (68.2 105. a parasite commonly found in New World monkeys.888 10.864 4.450 12. Identification was confirmed by PCR.100 11. In the recent past. In areas of South America where humans and monkeys coexist.3 1 13 5 11 27 11 7 18 19 13 9 21 22 23 20 11 12 19 11 23 23 22 21 11 26 13 11 18 10 10 10 15 12 19 16 23 18 20 10 15.0 0 8 1 2 9 2 1 8 15 8 6 16 19 15 11 11 2 8 7 13 15 19 13 7 17 10 5 8 6 6 6 9 8 10 7 13 15 14 6 9. malariae was prevalent in Europe and in southern parts of the United States. MICROBIOL. malariae that has naturally adapted to grow in monkeys following human settlement of South America within the last 500 years.418 11.0 106. This parasite is apparently the same species as P. Plasmodium malariae is wide spread throughout sub-Saharan Africa.0 106.976 15. careful microscopic examination may not be sufficient for positive confirmation in certain situations where monkey malaria parasites such as P.170 6.350 10. P. these grow slowly but soon occupy one-fourth to .8 106. Parasite counts and fever for 39 patients infected with Plasmodium malariae following previous infection with P.500 12. 108). means are shown for the other parameters.1 105. in fact. In many instances.350 9.510 16.0 105.

29.4 105. 107. 59. but the average number is 8. A. The nuclei and cytoplasm begin to separate. 120b. 113 3. ovalea Patient Days with parasitemia Maximum parasitemia (/␮l) Days with parasitemia of Ͼ1. A. 69. The parasite completely fills the host cell. and it often stretches across the host cell to form what is known as the band form. 114 64. A. 111 47a 25. A. 98. one-third of the parasitized cell. 121 10b. A. At about the 54th hour. Burma. Southeast Asia Malaysia Africa Europe Southeast Asia. 12b. 122 5b. The TABLE 5. 63. A. Myanmar India.41 104.2 105. 25. 121b. 32. 112 47a 81b 3 47a 50 79. or meanb a b 485 134 97 96 14 21 196 48 14–485 1. 113 Listed by Garnham (47). 29. A. 66. pigment is scattered. A. and the pigment becomes segregated and clumped in a loose mass in the center of the cell surrounded by the more or less symmetrically arranged merozoites. Pigment increases rapidly. 32.575 6 56 63 26 11 11 57 25 31. A. 33. aconitus annulipes arabiensis atroparvusb aztecus claviger culicifacies darlingi dirus farauti fluviatilis freebornib fuliginosusc funestus gambiae hyrcanus sinensis jeyporiensis lindesayi maculatus melas messeaeb minimus moucheti plumbeus punctulatusb punctipennis quadrimaculatusb saccharovib splendidus stephensib sundiacusb varuna 99 47a 29 17. 32.477 5. A. India Western United States Southeast Asia Africa Africa Southeast Asia. A. Southeast Asia. 103b.0 102. The number of merozoites may be from 6 to 14.960 23.050 18. 89 47a 24. means are shown for the other parameters. A. 113 47a 30. A. 64. These are often considered diagnostic. A. A. A. The mature macrogametocyte has a dense. reference not given.0 105. 64. 32. A. A. 34.100 16. Species of Anopheles mosquitoes that have been infected with Plasmodium malariae Geographic region Species of Anopheles References(s) Southeast Asia Australia Africa Europe Mexico Europe.VOL. 33 37. 6. A. A.6 105. 64. The pigment is scattered. 122b 3. A. 88 3.8 106. A. Indonesia Bangladesh.040 6.000/␮l Days with fever of Ն101°F Maximum fever (oF) Days with fever of Ն104°F S-1293 S-1278 S-1106 S-1271 S-1092 S-1305 S-1273 S-1264 Range. 33. A.60 105. 32. A. The host cell is not enlarged as the parasite grows to fill the infected erythrocyte. 29. A. 121b. Parasite counts and fever for eight patients infected with Plasmodium malariae following previous infection with P. 106b 121 57 29. and the half-grown parasite may have from 30 to 50 jet-black granules. median. 33. . Asia. 70.8 105. deeply staining blue cytoplasm with a small red-staining nucleus. 56. fuligenosis ϭ A. A. 39. Indonesia Africa Europe Australasia Southeastern United States Southeastern United States Europe Southeast Asia Middle East. 11b. segmentation begins. 29. Indonesia India a b c A. A.6 0 3 11 5 1 4 12 7 5. 29. Middle East India. 25. and by the 65th hour. A. 33. A. Sri Lanka South America Thailand Southwest Pacific Middle East.4 Data are from reference 83. 65. annularis. A. it assumes various shapes. 20. 2007 PLASMODIUM MALARIAE: PARASITE AND DISEASE 585 TABLE 4. 40b. 73. 16b. Range and median are shown for days with parasitemia and maximum parasitemia. Transmission to human reported. the host cell is nearly filled and the parasite contains five or six chromatin masses. A. As the parasite grows.166 18. 86b 3 25. 25. 80b 82. A.9 5 14 29 17 6 7 21 13 14.486 13.350 11. 31. 104. 114 47a 3 3. 18b. 34. 42b. although they are sometimes seen in other species.

They allow for the measurement of past exposure to infection. falciparum with sera from individuals 13 years of age and older. which shows promise for the detection of minority species in infections with mixed Plasmodium species. and 17-day oocysts and sporozoites. microgametocytes outnumber the macrogametocytes. cytoplasm of the adult microgametocyte has a light bluish pink stain. Ordinarily. Preservation The preservation of viable malaria parasites by freezing made possible the study of these organisms without continuous cyclical passage. 5 (27). Thick and thin blood films for immunofluorescence studies and teaching can be stored unfixed and frozen for extended periods. there was an almost complete absence of P.2% had positive responses to P. malariae. malariae infections has prompted alteration of the species-specific primers for this parasite. SEROLOGIC STUDIES Serologic tests are not specific enough for diagnostic purposes but are basic epidemiologic tools. 10-. subsequent infections were most frequently induced by the injection of parasitized erythrocytes that had been stored frozen over liquid nitrogen. Blood stages were stored for 20 and 60 days at a temperature of Ϫ70°C. Top row.. (85) described a PCR/ligase detection reaction fluorescent-microsphere assay for the diagnosis of infection levels with all four species of human malaria. (74). Failure to detect some P. a parasite of macaques from southeast Asia. malariae-infected erythrocytes has now become routine. malariae infection during a parasitologic survey. Parasites are usually stored in Glycerolyte (Baxter Healthcare Corp. malariae. However. 11-. the response soon declined. The high incidence of maximum IFA responses (51%) to P. was probably more indicative of the malarial experience or of subpatent parasitemia than the slide survey because of recent drug interventions (38). The immunofluorescent-antibody (IFA) technique has been used to measure the presence of antibodies to P. Jeffery and Rendtorff (67) reported the frozen preservation of blood stages of P.586 COLLINS AND JEFFERY CLIN. and may occupy half the infected cell. The pigment is limited to the cytoplasm of the parasite. FIG. and 13-day oocysts. Cross-reaction studies indicated that P. 3. Recent efforts have been directed towards the development of real-time PCR assays. REV. Serologic studies were subsequently conducted for responses to CS proteins of P. brasilianum (35). MICROBIOL. Rougemonet et al. However. Once the infections were established in chimpanzees and New World monkeys. malariae. The parasite appears to occupy the entire host cell. 43. malariae (26). brasilianum. In a serologic study of 498 sera collected from Nigerians. the monkey malaria parasite from South American monkeys that appears to be identical to P. 15-. malariae by using the CS repeat (NAAG)5 in an enzymelinked immunosorbent assay (ELISA). 12-. malariae. IL) and are expected to be viable for decades when held at extremely low temperatures over liquid nitrogen. Snounou et al. Plasmodium fieldi. takes a pinkish-blue stain. as shown in Fig. using genus. (109) applied the nested PCR technique to the diagnostic identification of all four human-infecting species of Plasmodium. also cross-reacted strongly with P. if the parasite count recrudesced or reinfection occurred. 14-. The nucleus is diffuse. which was highly specific and sensitive. In a study of a jungle aboriginal area in Malaysia. could be used in serologic testing (26). whereas historically the incidence was known to be quite high (38). It was shown that when an infection was of short duration.and species-specific primers targeting the 18S rRNA gene. often after many years of storage. Development of oocysts of Plasmodium malariae in Anopheles freeborni mosquitoes. In 1955. the IFA response rose to a higher lever and persisted for many months or years.. however. frozen blood is unsuitable for the preparation of blood films for microscopic diagnosis. In a study in Asembo . The frozen preservation of P. The response was low in children but was equal to that to P. bottom row. Fenwal Div. malariae was first described by Lal et al. (97) used a set of generic primers targeting a highly conserved region of the 18S rRNA genes of the four human-infecting species of Plasmodium to develop such an assay. McNamara et al. The structure of the circumsporozoite (CS) gene of P. Deerfield.

2 to 5. 12 and 13. (21) produced a hybridoma secreting a monoclonal antibody against the CS protein of P. (Reprinted from reference 20. malariae. developing schizonts. (41) found that almost all Metuktire and almost 90% of the Asurini adults had antisporozoite antibodies against P. 5. In a seroepidemiologic study conducted on Indian tribes in the Amazon Basin of northern Brazil. MOLECULAR STUDIES Cochrane et al. respectively. malariae to New World FIG. P. malariae was sequenced and shown to contain unique regions that could be used as diagnostic probes (55). by deletion of 19 bp and seven substitutions of base pairs in the target sequence (76). Thus. there appear to be two different types or potentially two subspecies of P. Beier et al. identified 3. malariae (Uganda I/CDC strain). mature microgametocyte. and P. INFECTIONS IN CHIMPANZEES AND MONKEYS Attempts to infect Old World monkeys have been unsuccessful. malariae sporozoites were then used to develop a two-site. 6 to 11. 4.) Bay. malariae. brasilianum/P. 14 to 20. falciparum. A two-dimensional electrophoretic assay showed that the CS protein recognized by the monoclonal antibody contains a repetitive epitope. malariae. singleantibody-based ELISA to detect sporozoites in mosquitoes (22). Kenya. growing trophozoites. Studies on the gene encoding cytochrome b from the linear mitochondrial genome indicated that P.2% of infected Anopheles gambiae sensu lato and A. mature schizonts. A gene encoding the small-subunit rRNA of P. There are few genomic data on this parasite. (7). normal red cell. Development of the IFA response in a patient following infection and recrudescence of an infection with Plasmodium malariae. all positivity rates increased with age (43). 1. 20. The first adaptation of P. the length of the CS protein gene varied due to the number of tandem repeat units (115). malariae. 24. The antibody also reacted strongly with sporozoites of the simian parasite P. Monoclonal antibodies specific for a repeat epitope of the CS protein of P. based on molecular differences in Asian parasites. Development of the erythrocytic stages of Plasmodium malariae. young trophozoites. A monoclonal antibody specific for the repeat epitope of the CS protein of P. . with two different minor repeats. 25. The major repeat was determined to be Asn Ala Ala Gly (NAAG). vivax. malariae was developed to detect sporozoites in FIG. mature macrogametocyte. brasilianum but did not bind to sporozoites of P. malariae was separate from other members of the primate-infecting Plasmodium species (46). 23. 59% of persons had antibodies to the peptide. demonstrating that periodicity is convergent in the evolution of the genus. The (NAAG)5 ELISA has also been used extensively. Asn Asp Ala Gly (NDAG) and Asn Asp Gln Gly (NDEG). developing gametocyte. malariae do not form a monophyletic group. Plasmodium inui and P. Arruda et al. funestus mosquitoes collected in western Kenya as being infected with P. In a study in Cameroon. 21 and 22. Studies indicated a variant form in the small-subunit rRNA gene sequence in the Sichuan province of China and along the Thai-Myanmar border. Recrudescence of infection began at day 84. nearly mature and mature trophozoites. for example. ovale. This has proven to be a valuable epidemiologic tool in identifying potential vectors of P. 2007 PLASMODIUM MALARIAE: PARASITE AND DISEASE 587 infected mosquitoes (22).VOL.

In 1939. 101. Following the infection of 49 animals that had been previously infected with both P. the median maximum parasite count with P. maximum parasite counts with P. PATHOLOGY Watson in 1905 (117) noted the presence of edema in a patient with malaria in Malaysia. 61. 94. In 29 monkeys that had been previously infected with P. . (61) graded the severity of pathological changes based on the percentage of glomeruli showing lesions. they did not show a response to therapy.700 per ␮l (29). Many investigators (9. (48) observed a maximum parasite count of 160. Blacklock and Adler (8) in 1922 in Sierra Leone and Schwetz (100. malariae in these animals. 6. Infections were infective to a variety of mosquito species on more than 50% of the days on which they were fed. 53. (1) examined the kidneys of Aotus monkeys infected with P. 51. The median maximum parasite count depended on the previous heterologous malarial experience of the animals. malariae was only 899/␮l. the median maximum parasite count was 6. Splenectomized chimpanzees were shown by Rodhain (95) and Garnham et al. they responded to therapy. If patients had up to 30% of glomeruli showing lesions. recrudescence occurred. vivax and P. subsequent transmission studies with quartan parasites isolated from chimpanzees convinced investigators that this parasite was actually P. rodhaini to the quartan parasite that infected chimpanzees and gorillas. Brumpt (15) gave the name P. malariae. Hendrikse and Adeniyi (60) described the clinico-pathological features associated with infection with P.760/␮l. FIG. MICROBIOL. In most instances. When 18 Aotus monkeys with no previous history of infection were infected with P. However. vivax and P. and mosquito infection was readily obtained (Fig. 28. monkeys was reported by Geiman and Siddiqui (49). Daily parasite counts and percent infection of Anopheles freeborni mosquitoes when fed on a splenectomized Aotus lemurinus griseimembra monkey infected with the Uganda I strain of Plasmodium malariae. Additional studies were made with different species of Aotus and Saimiri monkeys (23. and subsequently the relationship between P.488/␮l. malariae. Splenectomized Saimiri boliviensis monkeys had maximum parasite counts that varied from 62/␮l to 22. Histologically. the maximum parasite count with P. Electron microscopy revealed electron-dense deposits in the subendothelial and mesangial areas. 110) indicated a close relationship between quartan malaria and renal disease. 93. (48) to be readily infected. The renal disease tended to become chronic and nonresponsive to treatment with antimalarial and immunosuppressive drugs. Parasitemia often persisted for many weeks. 102) in the Belgian Congo also saw P. ovale. malariae and demonstrated that the nephrotic syndrome seen in monkeys was consistent with that seen in humans. The essential lesions are a thickening of the glomerular basement membrane and endocapillary cell proliferation (61. In 46 monkeys that had been previously infected with P. In a study with 31 splenectomized chimpanzees with various previous histories of infection with P. This gives rise to a double-contour or plexiform arrangement of periodic acid-Schiff stain-positive. falciparum. 33.588 COLLINS AND JEFFERY CLIN. 96).000 and 50.134/␮l. glomeruli of these monkeys infected with P. REV. Reichenow (91) studied malarias in chimpanzees and gorillas in the Cameroons and found P. 6). As the disease progresses. 52. Aikawa et al. infection was obtained when the parasite count was rising and diminished as soon as the count peaked. from 10 to 56. falciparum. 71). and the lesions extend to cause progressive narrowing and eventually complete obliteration of capillary lumens. In splenectomized Aotus monkeys. 36). malariae and suggested that immune complexes may cause structural glomerular damage. malariae was 1. 119). malariae infection and the nephrotic syndrome has been well documented. the median maximum parasite count was 13. Electron microscopy shows thickening of the glomerular basement membrane with an increase in the basement membrane-like material of varying density in the subendotherial zone (2). if they had greater than that. malariae varied markedly. malariae showed thickening and reduplication of the basement membrane and endocapillary cell proliferation. Hendrickse et al. However. similar to that of humans infected with P. 32. Dixon (44) demonstrated immune complexes in the kidneys of patients with nephrotic syndrome associated with quartan malaria. argyrophilic fibrils (45. vivax. malariae. maximum parasite counts following inoculation with a strain of P.270/␮l.800/␮l. malariae from Uganda ranged from 930 to 75. Bray (14) observed parasite counts in splenectomized animals of between 25. malariae (92. The changes were consistent with membranoproliferative glomerulonephritis. In 1920. more capillaries become affected. and Garnham et al.000 per ␮l.000 per ␮l. 34.

malariae sporozoites. the monkey-infecting malaria parasite of South America. It was detected on the inner surface of peripheral vacuoles during oocyst maturation and on the plasma membrane of the sporoblast. probably is an adaptation of P. Salivary gland sporozoites and sporozoites in mature oocysts were labeled uniformly on the outer surfaces of their plasma membranes. malariae to determine ultrastructural localization of this protein in midgut oocysts and salivary gland sporozoites.VOL. malariae to New World primates with the . 20. middle row. Antibodies against P. Top row. Morphological evidence suggested that proteins are transported between the erythrocyte surface and intracellular parasites via two routes: one associated with Maurer’s clefts for transport of membrane-associated knob material and a second associated with caveolae in the host cell membrane for the import or export of host. RELATIONSHIP TO OTHER SPECIES Malaria parasites of primates are organized based on biologic characteristics. brasilianum CS protein reacted with P. ULTRASTRUCTURE Ultrastructural studies have also been made on the erythrocytic stages of P. Nagasawa et al. trophozoite stages of Plasmodium malariae. malariae and on the oocyst and sporozoite stages in the mosquito. (4) indicated that P. trophozoite stages of Plasmodium inui. Atkinson et al. bottom row. There were highly structured arrays of merozoite surface coat proteins in the cytoplasm of early schizonts and on the surface of budding merozoites. Knobs were present in the membranes of Maurer’s clefts. (90) used immunoelectron microscopy and a monoclonal antibody for the CS protein of P. 2007 PLASMODIUM MALARIAE: PARASITE AND DISEASE 589 FIG. The CS protein was found along the capsule of immature oocysts but rarely within the cytoplasm.or parasite-derived substances through the erythrocyte cytoplasm. trophozoite stages of Plasmodium knowlesi. Plasmodium brasilianum. malariae was morphologically indistinguishable and structurally similar to other primate malaria species. 7.

Skinner.. MD. Hyg. C. Development of antibodies to Plasmodium malariae. A parasite resembling Plasmodium falciparumin a chimpanzee. Bray. Identification of malaria species by ELISA in sporozoite and oocyst 8. 20:247–257. 20:749–798. Hyg. B. V. Roberto. Collins. R. Stratman-Thomas. The experimental transmission and pre-erythrocytic phase of Plasmodium malariae. Pappaioanou. Observations on naturally and artificially induced quartan malaria. 1987. with a note on the host-range of the parasite. if from a human. K. Roum. malariae is closely related to any of the other primate malaria parasites that have been thus far examined (except P. Guinn. Morris. Parasitol. Warren. Adams. Bray. B. Malariology.. C.. E. Marsh. E. p. S. and G. 7. and J. and C. J. Collins. Med. W. J.. Med. K. and P. Trop. Experimental studies on the infectibility of anopheline mosquitoes of Formosa. J. Assoc. P. Hyg. J. M. infected Anopheles from western Kenya. McClure. and S. J. G. R. Boyd. E. A. Sullivan. Campbell. J. Trop. . M. 31. Huong. M. Trop. 1964. Am. Howard. R. Igarashi.. Am. 24. 55:1253–1257. W. M. G. and P. Philadelphia. B. and A. (inland variety) to the parasites of human malaria. which rarely exhibits mature forms in the peripheral blood. and C. S. Richardson. both of which result in enlargement of the host cell erythrocyte and prominent stippling. Med. Microbiol. Taylor. Rock. and many different mosquito vectors are capable of transmitting the parasite to humans. 83:1099–1103. 19. and W. De Petrise. M. Campbell. G. 1966. p. R. 22:685–692.. Cambournac. F. W. Broderson. brasilianum). J. IV. S. E. C. Contacos. E. Lupascu. The ready passage of P. W. 50:28–32. 1939. 9:68–71. Jeffery. J. it would be difficult to separate infections with monkey malaria parasites such as P. Negulici.. Richardson. A. C. K. Biol. 1933. E.. L. J. 7. 39:323– 327. 1940. Arch. Baretto. L. 38:283–288. G. B. R. Hyg. R. Parasitol. Collins. 18. Am. s. 15:11–15. W. E. 25. Lda. W. 1997. 15. 1966. and R. E. C. Galland. C. B. M. and P. Trop. 23:763–776. 1922. J. 1934. 2:679–680. Thus. S. Trop. P. E. inui. Houba. Trop. G. D. The transmission of quartan malaria through two consecutive human-anopheline passages. S. Wilson. ovale. P. vol. Infection of Anopheles freeborni mosquitoes on New World monkeys infected with the Uganda I/CDC strain of Plasmodium malariae. J. C. J. B. 20. E.. R.. Parasitol. P. 1949. brasilianum sporozoites. 33. Edington. Roberts. Parasitol. Hyg. H. E. G. and J. Jeffery. Sociedade Industrial de Tipografia. inui from those with P. Collins. E. Only the proximity of monkeys would have suggested a secondary examination by PCR or subpassage to susceptible monkeys to confirm infection with a Plasmodium species other than P. 1969. K. L. P. M. King. vivax and P. 16. P. Washington. Med. 75:61–65.. J. 2.. R. G. Aikawa. 3. Recherches sur la transmission expe ´rimentale de P. Bethesda. Sullivan. B. 9:379–381. Experimental infection in man with Plasmodium malariae. W. B. J. V. W. 1959. B. E. So ˆbre a epidemiologia do sezonismo em Portugal. W. Med.. Schwartz. Brumpt. W. R. J. B. 13: 265–271. brasilianum. Adams. Saunders Co. Am. 21. E. India 5:31–51. 28. the diagnostician would be left with P. Infectivity of Plasmodium malariae to different anophelines. J. and R. Exp. 29. H. J. and S. Stanfill. Lobel. 1973. 22. Collins. P. Whether or not such transmission occurs in nature has not been demonstrated. The human parasites of the genus Plasmodium. National Institutes of Health. J. J. F. knowlesi and P. Collins. Collins. introduction of Old World humans to the New World. K. 70:677–681. 1993. I. Les parasites du paludisme des chimpanze ´s. Pre-erythrocytic stages of human malaria parasites: Plasmodium malariae. G. Galland. Sullivan. C. Richardson. REV. J. Fluorescent antibody studies in human malaria. malariae. Ann. Skinner. Chin. Richardson. and the evolutionary origin of the species is unclear. 130:837–840. I. particularly if reliance on a thick blood film diagnosis was made. 1930. 23. W. Skinner. Richardson. F. Skinner. G. Trop. Filipski. J. Roberts. brasilianum are either the same species or variants of the same species. C. This is illustrated in Fig. 1975. with Plasmodium malariae and P. there is no indication of a close relationship to other primate-infecting species of Plasmodium. and P. Jacobs. Basu. Infect. G. Collins. E. 1969. J. and W. Richardson. E. R. K. F. 10.. would have immediately ruled out infection with P. Immun. Collins. Infectivity of Plasmodium malariae in the Aotus trivirgatus monkey to Anopheles freeborni mosquitoes. 1989. Stratman-Thomas. M. 12. Plasmodium inui. C.. Collins. H. J. B. Y. Contacos. Studies on malaria in chimpanzees. and H. G. Epid. McClure. A. Galland.. malariae as the probable diagnosis. Am. E. Control Assoc. Perkins. W. 42:99–103. 1994. VIII. Collins. J..590 COLLINS AND JEFFERY CLIN. PA. B. M. Broderson. Skinner. Plasmodium malariae appears to represent an independent colonization of humans by malaria parasites (46). 14. Morphologically. Strobert. J. C. I.. J. Onyango. Ultrastructure of the erythrocytic stages of Plasmodium malariae. C. 1–97. malariae ` a l’homme. Med. The Uganda I/CDC strain of Plasmodium malariae in Aotus lemurinus griseimembra monkeys. J. E... Collins. McClure. R. However. S. H. This parasite is also experimentally transmissible to humans (19). Formosa 30:609–632. 4. S. M. C. C. Boyd. Skinner. I. Am. M. Studies on the Uganda I/CDC strain of Plasmodium malariae in Bolivian Aotus monkeys and different anophelines. B. Morris. 9:455–465. Strobert. S. Plasmodium malariae and P. American Institute of Biological Sciences. brasilianum to humans and the passage of P. G. 1942. Allison. B. Med. Hyg. A note on the transmission of quartan malaria by Anopheles quadrimaculatus. Microbiol. 1931. B. 1988. and of Anopheles crucians Wied.. Monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) for detection of Plasmodium malariae sporozoites in mosquitoes. M. Am. K. Hendrickse. The comparative susceptibility of Anopheles quadrimaculatus Say. G. Contacos. Adler. Coatney. Med. Collins. G. Averbouch. and W. P. W. Mosq. Malaria Inst. malariae to New World monkeys indicated that such interspecies transmission between primates and humans is both feasible and probable. Am. B. D. Med. monkeys are commonly found to be infected with P. 13:l–5. 13. 9. Campbell. 52:660–663. Beier. The primate malarias. malariae was prevalent. J. There is no molecular evidence suggesting that P. An atlas of renal disease in Aotus monkeys with experimental plasmodial infection. H. P. Chin. Flipski. J. E. G. Collins. Am. Broderson. a quartan-type malaria parasite of Old World monkeys transmissible to man. E. Hyg. Broderson. F. Parasitol. Trop. J. Procell. Boyd. H. Blacklock. G. Nussenzweig. which shows the blood stages of P. M. E. A. 17. 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