Pathogenesis of malaria

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Official reprint from UpToDate www.uptodate.com 2011 UpToDate

Pathogenesis of malaria
Author Danny A Milner, Jr, MD Section Editor Johanna Daily, MD, MSc Deputy Editor Elinor L Baron, MD, DTMH

Last literature review version 19.1: enero 2011 | This topic last updated: septiembre 22, 2010 INTRODUCTION Understanding the pathogenesis of malaria requires investigation of mechanisms for parasite invasion and host defense. The parasite life cycle illustrates the interplay of parasite and host interactions (figure 1). Pathogenesis of P. falciparum is the area of greatest study, since this species causes the most severe clinical disease (other species include P. ovale, P. vivax, P. malariae and P. knowlesi). P. knowlesi malaria can also cause life threatening illness [1]. Issues related to the pathogenesis of malaria will be reviewed here. Issues related to epidemiology, clinical manifestations, diagnosis and treatment are discussed in detail separately. (See related topics). THE PARASITE Life cycle Human malaria occurs by transmission of Plasmodium sporozoites via a bite from an infected anopheline mosquito (figure 1). The sporozoites travel from the salivary glands of the mosquito through the bloodstream of the host to the liver, where they invade hepatocytes. These cells divide many 1000-fold until mature tissue schizonts are formed, each containing thousands of daughter merozoites. This exoerythrocytic stage is asymptomatic. The liver schizonts rupture after 6 to 16 days in P. falciparum (and there is typically a longer liver phase in other species) and release thousands of merozoites into the bloodstream, where they invade red blood cells of various ages (the erythrocytic stage). The merozoites mature successively from ring forms to trophozoites to mature red cell schizonts (asexual forms) over 24 hours (P. knowlesi), 48 hours (P. vivax, P. ovale, P. falciparum) or 72 hours (P. malariae). Within red blood cells the parasites digest red cell proteins, primarily hemoglobin. As hemoglobin is digested, the breakdown products are toxic to the parasite and, thus, hemozoin (a polarizable crystal) is formed in the food vacuole. The intracellular parasites modify the erythrocyte in several ways. They derive energy from anaerobic glycolysis of glucose to lactic acid, which may contribute to clinical manifestations of hypoglycemia and lactic acidosis [2]. They also make the red cell membrane less deformable, resulting in hemolysis and accelerated splenic

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clearance, which ultimately contribute to anemia. Alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of uninfected cells and contribute to anemia [3]. (See "Anemia in malaria".) Ultimately, new daughter merozoites are released from the infected erythrocytes. The remnants of cell membrane and the hemozoin crystal are phagocytized by circulating macrophages, an important first stimulus in the activation of the immune cascade [4,5]. In addition, free heme is released into the peripheral blood, an important stimulus for endothelial activation; endothelial cell damage also occurs in some patients [4-6]. Red cell lysis stimulates release of pro-inflammatory cytokines, including tumor necrosis factor (TNF). TNF suppresses hematopoiesis, which also contributes to the anemia. The liver and spleen enlarge over time; the spleen may become massively enlarged [7]. Thrombocytopenia is caused by a combination of hypersplenism (ie, increased splenic sequestration and decreased platelet survival time) and, in the case of P. falciparum, consumption of platelets in microvascular sequestration [8-11]. (See 'Coagulation' below.) Most released merozoites continue in the asexual cycle and infect new red cells, although a few differentiate into male or female gametocytes (sexual forms) which cause no symptoms but can circulate in the bloodstream until they are ingested by a blood-feeding anopheline mosquito. These sexual forms complete their life cycle within the midgut of the Anopheles mosquito, and the sporozoites that form then migrate to the salivary glands of the mosquito, from where they can reinfect humans. In the setting of P. vivax and P. ovale infection, some parasites remain dormant in the liver as hypnozoites and can cause late relapse by reactivating after many months [12]. In the setting of P. falciparum and P. malariae infection, hypnozoite parasites do not develop in the liver. However, P. malariae can cause very late relapse due to subpatent infection that can become symptomatic years to decades later. Genetic diversity Surveys of the P. falciparum genome from different geographic regions have demonstrated remarkable genetic diversity. The parasite genome is much more diverse than the human genome; single nucleotide polymorphisms, insertions/deletions, and microsatellites are very common in particular genes (genes that are under immune selection, for example) [13-15]. Using these polymorphisms as markers in genome-wide association studies allows identification of the source of clinical and experimental phenotypes of the parasites, improving understanding of pathogenesis and potential for development of new therapies. Variation in gene copy number among genes known to be involved in metabolic pathways may influence drug susceptibility [16]. Comprehensive genetic mapping will enable further identification of genes mediating drug resistance as well as

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potential vaccine targets. PATHOPHYSIOLOGY Microvascular disease and sequestration Cytoadherence to human cell surfaces is an important component of P. falciparum pathogenesis. As P. falciparum parasites mature from rings to trophozoites within red blood cells, they induce the formation of sticky knobs on the surface of erythrocytes [17,18]. The knobs are composed of a combination of parasite produced proteins including P. falciparum erythrocyte membrane protein-1 (PfEMP-1, the product of var gene expression and proposed primary cytoadherence factor), KAHRP, PfEMP-2, and RESA as well as human proteins including spectrin, actin, and band 4.1 [19-21]. Each P. falciparum parasite has 60 different var genes; of these, one protein product is present in individual parasites [22]. The knobs bind to receptors on a variety of cell types in capillaries and venules, including endothelial cells. Notable human receptors include ICAM-1 (vascular endothelium), CD36 (on endothelium and platelets), and CSA (in the placenta); a variety of other binding interactions have also been elucidated [23-26]. Endothelial binding leads to sequestration of infected red cells within these small vessels (thereby removing parasites from the peripheral circulation during a prolonged period of the life cycle). This leads to partial blood flow obstruction, endothelial barrier breakdown, and inflammation [17]. Sequestration can be demonstrated in any organ of a patient infected with P. falciparum. The most catastrophic clinical manifestation of sequestration is cerebral malaria. Renal failure in the setting of malaria may occur in part as a result of mechanical obstruction by infected erythrocytes; immune mediated glomerular pathology and fluid loss due to alterations in the renal microcirculation also probably contribute to renal failure [27]. Rosetting is another mechanism of microvascular disease. Infected red cells stick to uninfected red cells and form rosettes that clog the microcirculation [28,29]. Rosetting is mediated by an interaction between PfEMP-1 within knobs and receptors on the surface of uninfected red cells, such as complement-receptor 1 (CR1) [28,29]. Parasite biomass Vascular beds harboring sequestered parasites allow accumulation of high levels of parasite biomass in the host. HRP-2 (a P. falciparum antigen expressed on the erythrocyte membrane) can be used as an indirect measure of parasite biomass both in the circulation and sequestered in the microvasculature. The concentration of this antigen has been observed to correlate with severity of clinical disease [30]. Cytokines The interaction between host endothelium and immune cells with malaria parasites is complex and not fully understood. The "cytokine storm" hypothesis suggests that in the setting of severe malaria, damaging cytokines and small molecules become unregulated and lead to a SIRS-like state with high circulating levels of TNF and nitric oxide. However, evidence of direct correlation

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between severe malaria and the activity of these markers is limited. Some markers, such as the acute phase reactant C reactive protein (CRP), correlate directly with parasitemia. Cytokines TNF, lymphotoxin, interleukin(IL)-6, IL-10, IL-12, IL-18, and MIP-1 are consistently elevated in the setting of malaria. However, it is not clear whether these precede or follow clinical markers of severe infection. Molecular evidence for endothelial and tissue damage includes elevated levels of lactate, CK-MB, myoglobin, and angiopoietin-2 as well as increased soluble ligands/receptors (eg, sELAM-1, sICAM-1, sTNF-R1, sTNF-R2, sVCAM-1) [31]. Microparticles (small circulating bodies released from the surface of human cells) are another interesting component of pathogenesis; more data are needed to understand their exact role. Coagulation The initiation of tissue factor production in the coagulation cascade has been proposed as a unifying mechanism of pathogenesis in severe malaria, based on the following observations [8,32-34]: Thrombocytopenia is a common feature of severe malaria; it may also observed in uncomplicated malaria [8,32]. Activation of the coagulation cascade in the absence overt bleeding (eg, elevated D-dimer and thrombin-antithrombin complexes with normal prothrombin time and thromboplastin time) is also common [33]. Autopsies of patients with cerebral malaria frequently demonstrate fibrin microthrombi admixed with platelets in the cerebral vasculature (as well as other organs) [34]. Nitric oxide Low nitric oxide, low arginine (the pre-cursor of nitric oxide), and elevated arginase activity in peripheral blood have been observed in severe malaria [35]. Metabolic studies have demonstrated that the parasite's arginase enzyme (which converts arginine to ornithine) may contribute to hypoargininemia in severely ill patients, thus shutting down nitric oxide production [36]. Children with nitric oxide depletion due to intravascular hemolysis in the setting of malaria subsequently develop pulmonary hypertension and myocardial wall stress [35]. Replenishment of nitric oxide via peripheral arginine has been suggested as a possible treatment [37,38]. THE HOST Genetic factors Several genetic polymorphisms and mutations appear to influence the severity of malaria infection; examples are summarized in the Table (table 1). Hemoglobin and red cell antigens Hemoglobin and red cell antigens can confer variable protection against malaria. (See "Protection against malaria in the hemoglobinopathies".) A classic example is the Duffy blood group factor, a red cell antigen necessary

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for invasion by P. vivax [39]. Absence of the Duffy antigen on red cells (largely observed in individuals from West and sub-Saharan Africa) is protective for P. vivax malaria [39]. However, cases of P. vivax in Duffynegative individuals have been identified in Brazil and in Kenya, suggesting that P. vivax is evolving alternate red blood cell invasion pathways to invade Duffy-negative red cells [40,41]. There is strong evidence that sickle cell genetic alterations evolved in part because of the survival advantage against lethal P. falciparum infections [42-44]. Children with HbAS have a significantly lower risk of P. falciparum malaria, lower parasite densities, and lower rates of hospital admissions than children with HbAA [45]. Possible mechanisms are discussed in detail separately. (See "Protection against malaria in the hemoglobinopathies".) The potential protective effect of sickle hemoglobin against malaria may be augmented in malaria endemic areas; individuals outside endemic areas may have a lesser degree of protection. In a family living in the United States in which two children had sickle cell anemia and three had sickle cell trait, travel to an endemic region without chemoprophylaxis led to hemolytic crisis in three of the children [46]. Thalassemia may indirectly protect against P. falciparum infection by mediating increased susceptibility to nonlethal P. vivax, particularly in young children [47,48]. Red blood cells in individuals with thalassemia appear to be susceptible to P. falciparum invasion but are associated with significantly reduced parasite multiplication [49,50]. This may be due to the variable degree of persistence of hemoglobin F, which is relatively resistant to hemoglobin digestion by malarial hemoglobinases [48,51,52]. (See "Pathophysiology of beta thalassemia", section on 'Protection against severe malaria'.) Ovalocytosis in Southeast Asia appears to confer protection against malarial infection. Possible mechanisms include diminished invasion, poor intraerythrocytic growth, or diminished cytoadherence of infected erythrocytes [53,54]. Hereditary elliptocytosis appears to confer protection against malaria, although malaria infection in the setting of this condition has been described [55]. (See "Hereditary elliptocytosis: Genetics and pathogenesis", section on 'Resistance to malaria'.) The haptoglobin (Hp) genotype determines the efficiency of hemoglobin clearance after malaria-induced hemolysis. A particular polymorphism of the haptoglobin genotype (Hp2/2) has been associated with a reduction in the number of clinical malarial episodes; this was illustrated in a study of 312 children in Kenya [56]. Pyruvate kinase deficiency appears to be protective against infection and replication of P. falciparum in human erythrocytes. Therefore, mutant

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pyruvate kinase alleles may confer protection against malaria in endemic areas [57]. Tumor necrosis factor Polymorphisms in tumor necrosis factor (TNF) genes appear to influence the severity of P. falciparum infection [58,59]. This was illustrated in a study of about 1000 Gambian children; a sevenfold increased risk of severe neurological sequelae or death from cerebral malaria was observed among those who were homozygous for a polymorphism in the promoter region of the TNF gene (TNF2 allele). Severe anemia was associated with a different TNF allele, suggesting that different genetic factors affect susceptibility to these two disease manifestations [58]. Immunity Individuals living in endemic areas appear to develop partial immunity to malaria following repeated infections; the degree of protective immunity appears to be proportional to transmission intensity. Individuals in highly endemic areas (eg, sub-Saharan Africa) acquire nearly complete protection by early adulthood [60-62]. Individuals in low transmission areas (eg, Southeast Asia) remaining at risk for clinical infection and fatal disease into adulthood; these individuals are referred to as "semi-immune." Individuals not living in endemic areas (eg, travelers) infected with malaria form a detectable antibody response (which can be measured by ELISA), although this response is not protective against the initial infection of malaria and may serve only as a marker of past exposure [62]. Immunity in pregnancy is also important. The risk of parasitemia during the first years of life is higher among children born to multigravid women than primigravid women [63,64]. The immunologic basis for this observation is not fully understood. Humoral response The humoral immune response to malaria appears to correlate with severity of clinical infection, with progression in maturation of the humoral response in the setting of ongoing parasite antigen stimulation. Elevated levels of IgG4, IgE and IgM are associated with severe disease in individuals with 5 previous clinical episodes of malaria, while elevated levels of IgG (IgG, IgG1, IgG2 and IgG3) are associated with mild disease in individuals with >5 previous clinical episodes [65,66]. These observations suggest that persistence of humoral immunity requires ongoing parasite antigen stimulation. In addition, individuals who leave endemic areas appear to lose some humoral protection; these individuals are "semiimmune" and their protection is lessened when they return to endemic areas after prolonged periods without parasite antigen stimulation. (See "Prevention of malaria infection in travelers".) Cellular response The ability to mount a robust interferon-gamma response (predominantly through CD56+ gamma T-cells) has been associated with protection against high parasitemia [67]. Phagocytosis of hemozoin or trophozoites impairs the ability of monocytes and macrophages to mount oxidative

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burst, kill ingested bacteria, present antigens correctly, and mature to functioning dendritic cells [4]. These cells produce TNF and other proinflammatory cytokines, and release peroxidation derivatives of polyunsaturated fatty acids [4]. In addition, these cells have increase in activity and release of MMP-9, which is correlated with TNF- and IL-1 gamma production and leads to disruption of the basal lamina of endothelial cells [4,5]. SUMMARY Understanding the pathogenesis of malaria requires investigation of mechanisms for parasite invasion and host defense. The parasite life cycle illustrates the interplay of parasite and host interactions (figure 1). (See 'Introduction' above.) The plasmodium life cycle consists of an exoerythrocytic (asymptomatic) stage and erythrocytic (symptomatic) stage. Plasmodium sporozoites are transmitted by the bite of an infected anopheline mosquito. The sporozoites invade hepatocytes, which divide until schizonts are formed containing thousands of daughter merozoites. These rupture and release merozoites into the bloodstream, where they invade red blood cells. (See 'Life cycle' above.) Intracellular parasites alter the red cell, digesting hemoglobin to form hemozoin and making the membrane less deformable, resulting in hemolysis or splenic clearance. The merozoites invade the red cell and mature to ring forms, trophozoites, and schizonts. Schizonts rupture and release new daughter merozoites as well as pro-inflammatory cytokines including tumor necrosis factor (TNF). Most released merozoites infect new red cells; a few differentiate into gametocytes, which circulate until they are ingested by a mosquito to continue the transmission cycle. (See 'Life cycle' above and 'Cytokines' above.) Endothelial binding of infected red cells leads to sequestration of infected red cells within small vessels (thereby removing parasites from the peripheral circulation during a prolonged period of the life cycle). This leads to partial blood flow obstruction, endothelial barrier breakdown, and inflammation. Mechanisms of microvascular disease include formation of sticky knobs on the cell surface and rosetting (eg, adherence of infected red cells to uninfected cells, forming rosettes that clog the microcirculation). (See 'Microvascular disease and sequestration' above.) Several human genetic polymorphisms and mutations have been observed to influence the severity of malaria infection, particularly hemoglobin and red cell antigens. (See 'Genetic factors' above and "Protection against malaria in the hemoglobinopathies" and "Anemia in malaria".) Individuals living in endemic areas appear to develop partial immunity to malaria following repeated infections; the degree of protective immunity appears to be proportional to transmission intensity. The cellular immune

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response consists of a variety of cytokines including interferon-gamma and tumor necrosis factor. (See 'Immunity' above.) ACKNOWLEDGMENT The editorial staff at UpToDate, Inc. would like to acknowledge Drs. Peter Weller and Karin Leder, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis 2008; 46:165. 2. Daily JP, Scanfeld D, Pochet N, et al. Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 2007; 450:1091. 3. Brattig NW, Kowalsky K, Liu X, et al. Plasmodium falciparum glycosylphosphatidylinositol toxin interacts with the membrane of non-parasitized red blood cells: a putative mechanism contributing to malaria anemia. Microbes Infect 2008; 10:885. 4. Prato M, Giribaldi G, Polimeni M, et al. Phagocytosis of hemozoin enhances matrix metalloproteinase-9 activity and TNF-alpha production in human monocytes: role of matrix metalloproteinases in the pathogenesis of falciparum malaria. J Immunol 2005; 175:6436. 5. Prato M, Gallo V, Giribaldi G, Arese P. Phagocytosis of haemozoin (malarial pigment) enhances metalloproteinase-9 activity in human adherent monocytes: role of IL-1beta and 15-HETE. Malar J 2008; 7:157. 6. Ferreira A, Balla J, Jeney V, et al. A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 2008; 86:1097. 7. Bedu-Addo G, Bates I. Causes of massive tropical splenomegaly in Ghana. Lancet 2002; 360:449. 8. Wassmer SC, Taylor T, Maclennan CA, et al. Platelet-induced clumping of Plasmodium falciparum-infected erythrocytes from Malawian patients with cerebral malaria-possible modulation in vivo by thrombocytopenia. J Infect Dis 2008; 197:72. 9. Wassmer SC, de Souza JB, Frre C, et al. TGF-beta1 released from activated platelets can induce TNF-stimulated human brain endothelium apoptosis: a new mechanism for microvascular lesion during cerebral malaria. J Immunol 2006; 176:1180. 10. Wassmer SC, Combes V, Candal FJ, et al. Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum. Infect Immun 2006; 74:645. 11. Wassmer SC, Cianciolo GJ, Combes V, Grau GE. [LMP-420, a new therapeutic approach for cerebral malaria?]. Med Sci (Paris) 2006; 22:343. 12. Imwong M, Snounou G, Pukrittayakamee S, et al. Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis 2007; 195:927. 13. Volkman SK, Sabeti PC, DeCaprio D, et al. A genome-wide map of diversity in
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Plasmodium falciparum. Nat Genet 2007; 39:113. 14. Jiang H, Yi M, Mu J, et al. Detection of genome-wide polymorphisms in the AT-rich Plasmodium falciparum genome using a high-density microarray. BMC Genomics 2008; 9:398. 15. Mu J, Awadalla P, Duan J, et al. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol 2005; 3:e335. 16. Nair S, Miller B, Barends M, et al. Adaptive copy number evolution in malaria parasites. PLoS Genet 2008; 4:e1000243. 17. Newbold C, Craig A, Kyes S, et al. Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int J Parasitol 1999; 29:927. 18. Oh SS, Chishti AH, Palek J, Liu SC. Erythrocyte membrane alterations in Plasmodium falciparum malaria sequestration. Curr Opin Hematol 1997; 4:148. 19. Aikawa M. Morphological changes in erythrocytes induced by malarial parasites. Biol Cell 1988; 64:173. 20. Sharma YD. Knobs, knob proteins and cytoadherence in falciparum malaria. Int J Biochem 1991; 23:775. 21. Sharma YD. Knob proteins in falciparum malaria. Indian J Med Res 1997; 106:53. 22. Chookajorn T, Ponsuwanna P, Cui L. Mutually exclusive var gene expression in the malaria parasite: multiple layers of regulation. Trends Parasitol 2008; 24:455. 23. Chaiyaroj SC, Angkasekwinai P, Buranakiti A, et al. Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor. Am J Trop Med Hyg 1996; 55:76. 24. Maubert B, Guilbert LJ, Deloron P. Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta. Infect Immun 1997; 65:1251. 25. Rogerson SJ, Tembenu R, Dobao C, et al. Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria. Am J Trop Med Hyg 1999; 61:467. 26. Maubert B, Fievet N, Tami G, et al. Cytoadherence of Plasmodium falciparuminfected erythrocytes in the human placenta. Parasite Immunol 2000; 22:191. 27. Das BS. Renal failure in malaria. J Vector Borne Dis 2008; 45:83. 28. Chen Q, Schlichtherle M, Wahlgren M. Molecular aspects of severe malaria. Clin Microbiol Rev 2000; 13:439. 29. Rowe JA, Moulds JM, Newbold CI, Miller LH. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complementreceptor 1. Nature 1997; 388:292. 30. Dondorp AM. Clinical significance of sequestration in adults with severe malaria. Transfus Clin Biol 2008; 15:56. 31. Yeo TW, Lampah DA, Gitawati R, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A 2008; 105:17097.

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32. Taylor WR, Widjaja H, Basri H, et al. Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria. Malar J 2008; 7:259. 33. Francischetti IM. Does activation of the blood coagulation cascade have a role in malaria pathogenesis? Trends Parasitol 2008; 24:258. 34. Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu Rev Pathol 2007; 2:217. 35. Janka JJ, Koita OA, Traor B, et al. Increased pulmonary pressures and myocardial wall stress in children with severe malaria. J Infect Dis 2010; 202:791. 36. Olszewski KL, Morrisey JM, Wilinski D, et al. Host-parasite interactions revealed by Plasmodium falciparum metabolomics. Cell Host Microbe 2009; 5:191. 37. Weinberg JB, Lopansri BK, Mwaikambo E, Granger DL. Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr Opin Infect Dis 2008; 21:468. 38. Yeo TW, Lampah DA, Gitawati R, et al. Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations. J Infect Dis 2008; 198:602. 39. Miller LH, Mason SJ, Clyde DF, McGinniss MH. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med 1976; 295:302. 40. Ryan JR, Stoute JA, Amon J, et al. Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya. Am J Trop Med Hyg 2006; 75:575. 41. Cavasini CE, Mattos LC, Couto AA, et al. Plasmodium vivax infection among Duffy antigen-negative individuals from the Brazilian Amazon region: an exception? Trans R Soc Trop Med Hyg 2007; 101:1042. 42. Nagel RL, Fleming AF. Genetic epidemiology of the beta s gene. Baillieres Clin Haematol 1992; 5:331. 43. Flint J, Harding RM, Clegg JB, Boyce AJ. Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants. Hum Genet 1993; 91:91. 44. Aidoo M, Terlouw DJ, Kolczak MS, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002; 359:1311. 45. Williams TN, Mwangi TW, Wambua S, et al. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis 2005; 192:178. 46. Glikman D, Nguyen-Dinh P, Roberts JM, et al. Clinical malaria and sickle cell disease among multiple family members in Chicago, Illinois. Pediatrics 2007; 120:e745. 47. Williams TN, Maitland K, Bennett S, et al. High incidence of malaria in alphathalassaemic children. Nature 1996; 383:522. 48. Clegg JB, Weatherall DJ. Thalassemia and malaria: new insights into an old problem. Proc Assoc Am Physicians 1999; 111:278.

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49. Enevold A, Lusingu JP, Mmbando B, et al. Reduced risk of uncomplicated malaria episodes in children with alpha+-thalassemia in northeastern Tanzania. Am J Trop Med Hyg 2008; 78:714. 50. Veenemans J, Andang'o PE, Mbugi EV, et al. Alpha+ -thalassemia protects against anemia associated with asymptomatic malaria: evidence from community-based surveys in Tanzania and Kenya. J Infect Dis 2008; 198:401. 51. Pattanapanyasat K, Yongvanitchit K, Tongtawe P, et al. Impairment of Plasmodium falciparum growth in thalassemic red blood cells: further evidence by using biotin labeling and flow cytometry. Blood 1999; 93:3116. 52. Pasvol G, Weatherall DJ, Wilson RJ, et al. Fetal haemoglobin and malaria. Lancet 1976; 1:1269. 53. Gratzer WB, Dluzewski AR. The red blood cell and malaria parasite invasion. Semin Hematol 1993; 30:232. 54. Genton B, al-Yaman F, Mgone CS, et al. Ovalocytosis and cerebral malaria. Nature 1995; 378:564. 55. Boctor FN, Dorion RP. Malaria and hereditary elliptocytosis. Am J Hematol 2008; 83:753. 56. Atkinson SH, Mwangi TW, Uyoga SM, et al. The haptoglobin 2-2 genotype is associated with a reduced incidence of Plasmodium falciparum malaria in children on the coast of Kenya. Clin Infect Dis 2007; 44:802. 57. Ayi K, Min-Oo G, Serghides L, et al. Pyruvate kinase deficiency and malaria. N Engl J Med 2008; 358:1805. 58. McGuire W, Knight JC, Hill AV, et al. Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis 1999; 179:287. 59. McGuire W, Hill AV, Allsopp CE, et al. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371:508. 60. Dondorp AM, Lee SJ, Faiz MA, et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis 2008; 47:151. 61. Osier FH, Fegan G, Polley SD, et al. Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria. Infect Immun 2008; 76:2240. 62. Doolan DL, Dobao C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev 2009; 22:13. 63. Schwarz NG, Adegnika AA, Breitling LP, et al. Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis 2008; 47:1017. 64. Mutabingwa TK, Bolla MC, Li JL, et al. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med 2005; 2:e407. 65. Mibei EK, Otieno WO, Orago AS, Stoute JA. Distinct pattern of class and subclass antibodies in immune complexes of children with cerebral malaria and severe malarial anaemia. Parasite Immunol 2008; 30:334. 66. Leoratti FM, Durlacher RR, Lacerda MV, et al. Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria. Malar J 2008; 7:186.

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67. D'Ombrain MC, Robinson LJ, Stanisic DI, et al. Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin Infect Dis 2008; 47:1380.

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GRAPHICS
Plasmodium life cycle

1. Plasmodium-infected Anopheles mosquito bites a human and transmits sporozoites into the bloodstream. 2. Sporozoites migrate through the blood to the liver where they invade hepatocytes and divide to form multinucleated schizonts (pre-erythrocytic stage). 3. Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. This liver stage does not cause clinical symptoms, but with reactivation and release into the circulation, late onset or relapsed disease can occur up to many months after initial infection. 4. The schizonts rupture and release merozoites into the circulation where they invade red blood cells. Within red cells, merozoites mature from ring forms to trophozoites to multinucleated schizonts (erythrocytic stage). 5. Some merozoites differentiate into male or female gametocytes. These cells are ingested by the Anopheles mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary glands of the mosquito. The mosquito completes the cycle of transmission

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by biting another host.

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Gene polymorphism effects

Gene/polymorphism
LTA + 80

Effect/association
Parasitemia reduction

Theoretical mechanism
Lymphotoxin production Red cell signaling; invasion inhibition Decreased iNOS Unknown Decreased resetting of red blood cells Innate immunity

Ref.
[1]

GNAS

Severe malaria

[2]

INOS Pyruvate kinase ABO glycosyltransferase

Severe malaria Infection Severe malaria anemia

[3] [4] [5]

Toll-like Receptors (TLR-1, -6, and -9) FLT1 TIM1

Malaria and high parasitemia Placental malaria Cerebral malaria

[6]

Unknown Induction of Th2 anti-inflammatory responses Anti-inflammatory activity of enhanced IL-10 production Increased clearance of infected cells

[7] [8]

IL-10

Severe malaria anemia

[9]

CR-1 (promoter)

Cerebral malaria

[10,11]

1. Barbier, M, et al. Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium falciparum parasitemia. Microbes Infect 2008; 10:673. 2. Auburn, S, et al. Association of the GNAS locus with severe malaria. Human Genetics 2008; 124:499. 3. Dhangadamajhi, G, et al. The CCTTT pentanucleotide microsatellite in iNOS promoter influences the clinical outcome in P. falciparum infection. Parasitology Research. 4. Durand, PM, Coetzer, TM. Pyruvate kinase deficiency protects against malaria in humans. Haematologica 2008; 93:939. 5. Fry, AE, et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet 2008; 17:567. 6. Leoratti, FM, et al. Variants in the toll-like receptor signaling pathway and clinical outcomes of malaria. J Infect Dis 2008; 198:772. 7. Muehlenbachs, A, et al. Natural selection of FLT1 alleles and their association with malaria resistance in utero. Proc Natl Acad Sci U S A 2008; 105:14488.

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8. Nuchnoi, P, et al. Significant Association Between TIM1 Promoter Polymorphisms and Protection Against Cerebral malaria in Thailand. Annals of Human Genetics 2008; 72:327. 9. Ouma, C, et al. Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Hum Genet 2008; 124:515. 10. Cockburn, IA, et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci U S A 2004; 101:272. 11. Teeranaipong, P, et al. A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria. J Infect Dis 2008; 198:1880.

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