Relationship of Serum Complement Levels to Events of the Malarial Paroxysm

Neva, Franklin A.; Howard, Wayne; Glew, Richard H.; Krotoski, Wojciech A.; Gam, Albert A.; Collins, W. E.; Atkinson, John P.; Frank, Michael M.

doi:10.1172/jci107781

Cited by 41 publications

(8 citation statements)

References 15 publications

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“…Neva and colleagues found C activation occurred during or soon after schizont rupture and seemed to be dependent on the parasite density and presence of C fixing antibodies [20]. In the current study, activation of the C increased as the amount of supernatant used increased and then declined probably due to diminishing amounts of the C components, confirming presence of factors in the culture supernatant that have ability to activate C (Figure 2).…”

Section: Discussionsupporting

confidence: 78%

Complement Activation by Merozoite Antigens of Plasmodium falciparum

2014

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BackgroundComplement (C) is a crucial part of the innate immune system and becomes over activated during malaria, resulting in depletion of C components, especially those for lectin pathway (LP), thereby compromising the host's innate defense. In this study, involvement of P. falciparum antigens in C activation was investigated.MethodsA highly synchronous culture of the Dd2 clone of P. falciparum was established in a serum free medium. Supernatants harvested from rings, trophozoites and schizonts at various parasite densities were tested for ability to activate C by quantifying amount of C3b deposited on erythrocytes (E). Uninfected sham culture was used as control. Remnants of each C pathway were determined using Wieslab complement System Screenkit (Euro-diagnostica, Sweden). To identify MBL binding antigens of LP, culture supernatants were added to MBL sepharose columns and trapped antigens eluted with increasing concentrations of EDTA (10 mM, 50 mM and 100 mM) and then desalted before being tested for ability to activate C. The EDTA eluate with highest activity was run on a polyacrylamide gel and silver stained proteins analyzed by mass spectroscopy.ResultsAntigens released by P. falciparum growing in culture activated C leading to C3b deposition on E. Maximal activation at 7% parasitemia was associated with schizont stage (36.7%) compared to 22% for rings, 21% for trophozoites and 3% for sham culture. All the three pathways of C were activated, with highest activation being for the alternative pathway (only 6% of C activation potential remained), 65% for classiical and 43% for the LP. Seven MBL binding merozoite proteins were identified by mass spectrometry in the 50 mM EDTA eluate.ConclusionsMBL binding merozoite adhesins with ability to activate C pathway were identified. The survival advantage for such pronounced C activation is unclear, but opsonisation could facilitate recognition and invasion of E.

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Section: Discussionsupporting

confidence: 78%

Complement Activation by Merozoite Antigens of Plasmodium falciparum

2014

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“…Seminal findings on complement activation in malaria were published in the 1970s. Complement turnover was shown to be triggered in human patients suffering from severe malaria, 6 and experiments in monkeys demonstrated that complement consumption coincided with schizont rupture. 7 Clinical data now show that substantial complement activation occurs in human patients 8 and enhanced early complement activation in experimental human malaria has been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation

Dasari¹,

Heber²,

Beisele

et al. 2012

Blood

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Severe Plasmodium falciparum malaria evolves through the interplay among capillary sequestration of parasitized erythrocytes, deregulated inflammatory responses, and hemostasis dysfunction. After rupture, each parasitized erythrocyte releases not only infective merozoites, but also the digestive vacuole (DV), a membrane-bounded organelle containing the malaria pigment hemozoin. In the present study, we report that the intact organelle, but not isolated hemozoin, dually activates the alternative complement

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“…Severe malaria develops as a consequence of capillaric sequestration of parasitized RBCs (pRBCs), [1][2][3] activation of complement [4][5][6] and coagulation, [7][8][9] and increases in vascular permeability, which together can lead to microcirculatory disturbances with comatous death as the ultimate outcome. 1,7,10,11 One unresolved puzzle relates to the fact that children with severe malaria frequently suffer from septicemia due to bacteria that otherwise play no major role in this potentially fatal affliction.…”

Section: Introductionmentioning

confidence: 99%

Digestive vacuoles of Plasmodium falciparum are selectively phagocytosed by and impair killing function of polymorphonuclear leukocytes

Dasari

Reiß

Lingelbach

et al. 2011

Blood

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Sequestration of parasitized erythrocytes and dysregulation of the coagulation and complement system are hallmarks of severe Plasmodium falciparum malaria. A link between these events emerged through the discovery that the parasite digestive vacuole (DV), which is released together with infective merozoites into the bloodstream, dually activates the intrinsic clotting and alternative complement pathway. Complement attack occurs exclusively on the membrane of the DVs, and the question followed whether DVs might be marked for uptake by polymorphonuclear granulocytes (PMNs). We report that DVs are indeed rapidly phagocytosed by PMNs after schizont rupture in active human serum. Uptake of malaria pigment requires an intact DV membrane and does not occur when the pigment is extracted from the organelle. Merozoites are not opsonized and escape phagocytosis in nonimmune serum. Antimalarial Abs mediate some uptake of the parasites, but to an extent that is not sufficient to markedly reduce reinvasion rates. Phagocytosis of DVs induces a vigorous respiratory burst that drives the cells into IntroductionSevere malaria develops as a consequence of capillaric sequestration of parasitized RBCs (pRBCs), 1-3 activation of complement [4][5][6] and coagulation, 7-9 and increases in vascular permeability, which together can lead to microcirculatory disturbances with comatous death as the ultimate outcome. 1,7,10,11 One unresolved puzzle relates to the fact that children with severe malaria frequently suffer from septicemia due to bacteria that otherwise play no major role in this potentially fatal affliction. [12][13][14] Approximately 50% of these infections are caused by nontyphoidal Salmonellae and other Enterobacteriae, indicating a gut origin. Current hypotheses regarding the causes underlying this general state of immune compromise focus mainly on disturbances in the function of macrophages, dendritic cells, and the adaptive immune system. 15 During its developmental cycle in the RBC, the malaria parasite ingests hemoglobin and packages the waste product hemozoin, which is also known as malaria pigment, in an organelle designated the digestive vacuole (DV). 16 Copious numbers of DVs are released into the bloodstream in patients with severe Plasmodium falciparum malaria, yet their biologic properties and fates have been only minimally studied. Hematin is widely regarded to be equivalent to hemozoin, 17,18 and most investigators have focused on the effects of this artificial molecule on the immune system. [19][20][21][22][23][24][25] However, hematin is not packaged within a membrane-bound organelle and any biologic activity deriving from the DV membrane would therefore be missed. In a different study, we have shown that the DV membrane, but not hemozoin itself, is endowed with the unique capacity to dually activate the alternative complement and the intrinsic clotting pathway (P.D., S. Heber, S. Baumeister, K.L., K.R., S.C.B., and S. Bhakdi, unpublished data, September 2011). Overactivation of these ancient enzyme cascades ...

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Relationship of Serum Complement Levels to Events of the Malarial Paroxysm

Cited by 41 publications

References 15 publications

Complement Activation by Merozoite Antigens of Plasmodium falciparum

Complement Activation by Merozoite Antigens of Plasmodium falciparum

Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation

Digestive vacuoles of Plasmodium falciparum are selectively phagocytosed by and impair killing function of polymorphonuclear leukocytes

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