Membrane structure and function of malaria parasites and the infected erythrocyte

Sherman, Irwin W.

doi:10.1017/s0031182000062843

Cited by 106 publications

(37 citation statements)

References 135 publications

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“…Secreted malaria parasite proteins have to be transported across three bilayer membranes before getting out of the infected erythrocyte (42). In order to determine the release characteristics of rhIFN-␥, time course experiments were done in vitro.…”

Section: Discussionmentioning

confidence: 99%

TransfectedPlasmodium knowlesiProduces Bioactive Host Gamma Interferon: a New Perspective for Modulating Immune Responses to Malaria Parasites

et al. 2003

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Transgenic pathogenic microorganisms expressing host cytokines such as gamma interferon (IFN-␥) have been shown to manipulate host-pathogen interaction, leading to immunomodulation and enhanced protection. Expression of host cytokines in malaria parasites offers the opportunity to investigate the potential of an immunomodulatory approach by generating immunopotentiated parasites. Using the primate malaria parasite Plasmodium knowlesi, we explored the conditions for expressing host cytokines in malaria parasites. P. knowlesi parasites transfected with DNA constructs for expressing rhesus monkey (Macaca mulatta) IFN-␥ under the control of the heterologous P. berghei apical membrane antigen 1 promoter, produced bioactive IFN-␥ in a developmentally regulated manner. IFN-␥ expression had no marked effect on in vitro parasite development. Bioactivity of the parasite-produced IFN-␥ was shown through inhibition of virus cytopathic effect and confirmed by using M. mulatta peripheral blood cells in vitro. These data indicate for the first time that it is feasible to generate malaria parasites expressing bioactive host immunomodulatory cytokines. Furthermore, cytokine-expressing malaria parasites offer the opportunity to analyze cytokine-mediated modulation of malaria during the blood and liver stages of the infection.Recombinant pathogenic microorganisms expressing host cytokines such as gamma interferon (IFN-␥) have been shown to modulate immune responses, leading to enhanced protection (15-17, 19, 35, 43, 47). Vaccinia virus and simian immunodeficiency viruses expressing a range of host cytokines were attenuated in vivo, leading to enhanced immune responses (15-17), and Leishmania major expressing host IFN-␥ was significantly attenuated in nude mice (47). These data indicate that in vivo expression of host cytokines by pathogens can manipulate the host-pathogen interaction and generate protective host responses. Thus far, expression of host cytokines by malaria parasites has not been examined. The development of transfection technology for malaria parasites (18,49,51,54) now enables expression of recombinant host proteins, such as cytokines in Plasmodium.IFN-␥ is one of the central effector cytokines in host response to malaria infection, especially during the liver stage (14,21,33,(38)(39)(40) and hence is attractive for expression in malaria parasites. In vitro and in vivo studies in rodent models of malaria have demonstrated that IFN-␥ plays a central role in protection against malaria liver-stage infection, possibly by inducing the infected hepatocyte to produce nitric oxide that kills parasites (31,33). In clinical vaccination studies with an attenuated sporozoite vaccine (reviewed in reference 32), vaccinated humans were protected from subsequent infection through IFN-␥-dependent responses. In separate studies in mice and monkeys, sterile protection was achieved through IFN-␥-dependent responses after exogenous treatment with interleukin-12 (IL-12) (21, 39). Studies using rodent and human malaria models have demon...

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Section: Discussionmentioning

confidence: 99%

TransfectedPlasmodium knowlesiProduces Bioactive Host Gamma Interferon: a New Perspective for Modulating Immune Responses to Malaria Parasites

et al. 2003

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“…P falciparum particularly affects lipid composition of the infected red blood cell (IRBC) (cholesterol level, phospholipid pattern, organization, and degree of saturation) 1,2 but also its deformability and antigenic, osmotic, and transport properties. 3,4 Known consequences are sequestration and stiffness (involved in organ damage, eg, cerebral malaria) and removal. If these changes are well researched for IRBCs, little is known concerning the possible alterations in the membrane composition and structure of uninfected RBCs (URBCs) from patients with malaria or P falciparum in vitro cultures.…”

Section: Introductionmentioning

confidence: 99%

Accelerated senescence of human erythrocytes cultured with Plasmodium falciparum

Omodeo‐Salè

Motti

Basilico

et al. 2003

Blood

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Red blood cells infected with Plasmodium falciparum (IRBCs) undergo changes primarily in their membrane composition that contribute to malaria pathogenesis. However, all manifestations (eg, anemia) cannot be accounted for by IRBCs alone. Uninfected erythrocytes (URBCs) may play a role, but they have been underresearched. We wanted to document changes in the erythrocyte membrane that could contribute to URBC reduced life span and malaria-associated anemia. Human erythrocytes were cultured with P falciparum and washed at the trophozoite stage. IRBCs and URBCs were separated on Percoll density gradient, thus obtaining erythrocyte fractions of different densities/ages. IRBC-and URBCpurified membranes were analyzed and compared with control normal erythrocytes (NRBCs) of the same age, from the same donor, kept in the same conditions. P falciparum accelerated aging of both IRBCs and URBCs, causing a significant shift in the cell population toward the denser (old) fraction. Protein, phospholipid, and cholesterol content were reduced in IRBCs and young URBCs. Young and medium uninfected fractions had higher levels of lipid peroxidation and phospholipid saturation (because of the loss of polyunsaturated fatty acids, PUFAs) and lower phosphatidylserine. In IRBCs, thiobarbituric reactive substances (TBARSs) were higher, and PUFAs and phosphatidylserine lower than in NRBCs and URBCs. In comparison, trophozoite membranes had lower phospholipid (particularly sphingomyelin and phosphatidylserine) and cholesterol content and a higher degree of saturation. Parasiteinduced peroxidative damage might account for these modifications. In summary, we demonstrated that membrane damage leading to accelerated senescence of both infected and uninfected erythrocytes will likely contribute to malaria anemia. (Blood. 2003;102:705-711)

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“…This phenomenon has been described for different species of parasites and host cells: Plasm odium lophurae in duck red blood cells (Sherman andTanigoshi, 1974, 1975), P . berghei in mouse (Homewood and Neame, 1974) and P .…”

Section: Introductionmentioning

confidence: 78%

“…The intraerythrocytic development of malaria parasites involves dramatic changes in the structure and composition of the host cell membrane (see Sherman, 1985 for a recent review). One of the most obvious functional consequence of these changes is the permeabilization of the infected red blood cell to anions (Kutner .…”

Section: Discussionmentioning

confidence: 99%

Fractionation of Mouse malarious blood according to parasite developmental stage, using a percoll-sorbitol gradient

Ginsburg

Landau

Baccam

et al. 1987

Ann. Parasitol. Hum. Comp.

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SUMMARY.Asexual intraerythrocytic malarial parasites permeabilize the membrane of their host cell to small monelectrolytes and anions. Since permeabilization increases with parasite maturation, this property has been used previously to fractionate blood infected with Plasmodium falciparum and P. knowlesi according to the developmental stage of the parasite, using Percollsorbitol density gradients. We have extended this method to fractionate mouse blood infected with four species of rodent malaria: P. chahaudi, P. vinckei, P. voelii and P. berghei. While the method works in principle in this case, the polyparasitism which characterizes these species prevented explicit separation according to developmental stage. Hence, erythrocytes harbouring several ring-stage parasites appeared in the same fraction which contained cells hosting a single trophozoite, and polyparasitized trophozoites were associated with singly-infected schizont. This observation implies that permeabilization of the host cell membrane results from the inte grated metabolic activity of the parasite(s) and is not related to a specific phase of parasite development.

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Membrane structure and function of malaria parasites and the infected erythrocyte

Cited by 106 publications

References 135 publications

TransfectedPlasmodium knowlesiProduces Bioactive Host Gamma Interferon: a New Perspective for Modulating Immune Responses to Malaria Parasites

TransfectedPlasmodium knowlesiProduces Bioactive Host Gamma Interferon: a New Perspective for Modulating Immune Responses to Malaria Parasites

Accelerated senescence of human erythrocytes cultured with Plasmodium falciparum

Fractionation of Mouse malarious blood according to parasite developmental stage, using a percoll-sorbitol gradient

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