Immunosuppression in Malaria: Effect of Hemozoin Produced by &lt;i&gt;Plasmodium berghei&lt;/i&gt; and &lt;i&gt;Plasmodium falciparum&lt;/i&gt;

Morakote, Nimit; Justus, David E.

doi:10.1159/000234602

Cited by 35 publications

(27 citation statements)

References 3 publications

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“…This group of cells contains both macrophages and dendritic cells with increased phagocytic capacity (12). Phagocytosis of hemozoin pigment has often been implicated in malaria-associated immunosuppression (9,(16)(17)(18)(19)25), so it follows that phagocytic cells would be responsible for producing the observed soluble factor. While the nature of the soluble suppressive factor is not yet clear, our results and those of Scorza et al demonstrate that it is neither NO nor PGE 2 , two factors often implicated in suppression of IL-2 production (1, 2, 22-24).…”

Section: Discussionmentioning

confidence: 99%

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Antigen-Presenting Cell Function duringPlasmodium yoeliiInfection

et al. 2002

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Antigen-presenting cells (APC) play a key role in orchestrating immune responses. T-cell proliferative responses are inhibited during the erythrocyte stages of malaria infection, and a number of studies have suggested that APC are responsible for this phenomenon. In the present studies we examine individual components of the T-cell-activating function of APC: expression of costimulatory and major histocompatibility complex (MHC) class II proteins, the ability to process and present antigen to T cells, and the ability to support cytokine production. We find that during the acute phases of Plasmodium yoelii erythrocyte stage infection, APC upregulate the expression of class II MHC and CD80, maintain expression of CD86, process and present antigen, and support gamma interferon production. However the CD11b ؉ subpopulation produces a soluble factor or factors that specifically inhibit interleukin-2 (IL-2) production by responding CD4 T cells. This factor is distinct from prostaglandin E 2 , NO, or transforming growth factor ␤. The data suggest that IL-2 suppression observed during malaria infection is not due to functional defects of APC but is triggered by production of a factor(s) that actively suppresses production of IL-2 by T cells.

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Section: Discussionmentioning

confidence: 99%

“…The notion that macrophages from infected mice suppress T-cell proliferation has been a part of our understanding of malaria function for several decades (9,33), although the underlying mechanisms have been the subject of very few investigations. A similar phenomenon has been described for trypanosome infection (21,22).…”

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Antigen-Presenting Cell Function duringPlasmodium yoeliiInfection

et al. 2002

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“…Hemozoin, an insoluble by-product of hemoglobin proteolysis, has been reported to exhibit several biological effects that involve induction of proinflammatory mediators (reviewed in reference 107), dysfunction of monocyte/macrophages (108), modulation of the maturation of dendritic cells (109,110), immunosuppression (111,112), and suppression of erythropoiesis (113)(114)(115)(116)(117). To investigate the role of hemozoin deposition in the pathogenesis of severe malaria, we characterized the relationship between pigment-containing leukocytes, hemoglobin levels, and clinical severity.…”

Section: Fig 11mentioning

confidence: 99%

Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

et al. 2013

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f Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.

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“…In addition, trophozoites digest hemoglobin and detoxify the free heme to hemozoin which consists of crystallized Fe (III) protoporphyrin IX dimers. Engulfment of hemozoin by phagocytes reportedly alters the function of macrophages, monocytes and dendritic cells thus unfavorably influencing the clinical course of malaria [34][35][36][37][38]. Moreover, hemozoin-fed monocytes increase matrix metalloproteinase-9 activity fostering extravasation of phagocytic cells and parasitized erythrocytes into brain tissues [39].…”

Section: Introductionmentioning

confidence: 99%

Accelerated Clearance of Plasmodium-infected Erythrocytes in Sickle Cell Trait and Annexin-A7 Deficiency

Lang

Kasinathan

Brand

et al. 2009

Cell Physiol Biochem

125

108

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The course of malaria does not only depend on the virulence of the parasite Plasmodium but also on properties of host erythrocytes. Here, we show that infection of erythrocytes from human sickle cell trait (HbA/S) carriers with ring stages of P. falciparum led to significantly enhanced PGE₂ formation, Ca²⁺ permeability, annexin-A7 degradation, phosphatidylserine (PS) exposure at the cell surface, and clearance by macrophages. P. berghei-infected erythrocytes from annexin-A7-deficient (annexin-A7^-/-) mice were more rapidly cleared than infected wildtype cells. Accordingly, P. berghei-infected annexin-A7^-/- mice developed less parasitemia than wildtype mice. The cyclooxygenase inhibitor aspirin decreased erythrocyte PS exposure in infected annexin-A7^-/- mice and abolished the differences of parasitemia and survival between the genotypes. Conversely, the PGE₂-agonist sulprostone decreased parasitemia and increased survival of wild type mice. In conclusion, PS exposure on erythrocytes results in accelerated clearance of Plasmodium ring stage-infected HbA/S or annexin-A7^-/- erythrocytes and thus confers partial protection against malaria in vivo.

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Immunosuppression in Malaria: Effect of Hemozoin Produced by <i>Plasmodium berghei</i> and <i>Plasmodium falciparum</i>

Cited by 35 publications

References 3 publications

Antigen-Presenting Cell Function duringPlasmodium yoeliiInfection

Antigen-Presenting Cell Function duringPlasmodium yoeliiInfection

Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

Accelerated Clearance of Plasmodium-infected Erythrocytes in Sickle Cell Trait and Annexin-A7 Deficiency

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