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1.
PLoS Pathog ; 17(2): e1009259, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33600495

RESUMO

The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.


Assuntos
Cálcio/metabolismo , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Malária Falciparum/metabolismo , Monócitos/metabolismo , Fagocitose , Fosfatidilserinas/metabolismo , Membrana Eritrocítica/parasitologia , Eritrócitos/parasitologia , Humanos , Malária Falciparum/parasitologia , Monócitos/parasitologia , Plasmodium falciparum/isolamento & purificação
2.
Cell Mol Life Sci ; 78(10): 4545-4561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713154

RESUMO

Malaria is a vector-borne parasitic disease with a vast impact on human history, and according to the World Health Organisation, Plasmodium parasites still infect over 200 million people per year. Plasmodium falciparum, the deadliest parasite species, has a remarkable ability to undermine the host immune system and cause life-threatening disease during blood infection. The parasite's host cells, red blood cells (RBCs), generally maintain an asymmetric distribution of phospholipids in the two leaflets of the plasma membrane bilayer. Alterations to this asymmetry, particularly the exposure of phosphatidylserine (PS) in the outer leaflet, can be recognised by phagocytes. Because of the importance of innate immune defence numerous studies have investigated PS exposure in RBCs infected with P. falciparum, but have reached different conclusions. Here we review recent advancements in our understanding of the molecular mechanisms which regulate asymmetry in RBCs, and whether infection with the P. falciparum parasite results in changes to PS exposure. On the balance of evidence, it is likely that membrane asymmetry is disrupted in parasitised RBCs, though some methodological issues need addressing. We discuss the potential causes and consequences of altered asymmetry in parasitised RBCs, particularly for in vivo interactions with the immune system, and the role of host-parasite co-evolution. We also examine the potential asymmetric state of parasite membranes and summarise current knowledge on the parasite proteins, which could regulate asymmetry in these membranes. Finally, we highlight unresolved questions at this time and the need for interdisciplinary approaches to uncover the machinery which enables P. falciparum parasites to hide in mature erythrocytes.


Assuntos
Membrana Celular/metabolismo , Membrana Celular/parasitologia , Eritrócitos/metabolismo , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Fosfolipídeos/metabolismo , Plasmodium falciparum/patogenicidade , Animais , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita/fisiologia , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/parasitologia
3.
EMBO Mol Med ; 16(7): 1515-1532, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38862600

RESUMO

Parasites, such as the malaria parasite P. falciparum, are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and, therefore, serve as a successful treatment strategy. P. falciparum parasites cannot synthesise cholesterol, and instead source this lipid from the host. Here, we tested whether cholesterol uptake pathways could be 'hijacked' for optimal drug delivery to the intracellular parasite. We found that fluorescent cholesterol analogues were delivered from the extracellular environment to the intracellular parasite. We investigated the uptake and inhibitory effects of conjugate compounds, where proven antimalarial drugs (primaquine and artesunate) were attached to steroids that mimic the structure of cholesterol. These conjugated antimalarial drugs improved the inhibitory effects against multiple parasite lifecycle stages, multiple parasite species, and drug-resistant parasites, whilst also lowering the toxicity to human host cells. Steroids with introduced peroxides also displayed antimalarial activity. These results provide a proof-of-concept that cholesterol mimics can be developed as a drug delivery system against apicomplexan parasites with the potential to improve drug efficacy, increase therapeutic index, and defeat drug resistance.


Assuntos
Antimaláricos , Artesunato , Colesterol , Plasmodium falciparum , Colesterol/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Humanos , Artesunato/farmacologia , Artesunato/uso terapêutico , Primaquina/farmacologia , Primaquina/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Animais , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia
4.
Emerg Top Life Sci ; 7(1): 67-79, 2023 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-36820809

RESUMO

Eukaryotic pathogens with an intracellular parasitic lifestyle are shielded from extracellular threats during replication and growth. In addition to many nutrients, parasites scavenge host cell lipids to establish complex membrane structures inside their host cells. To counteract the disturbance of the host cell plasma membrane they have evolved strategies to regulate phospholipid asymmetry. In this review, the function and importance of lipid asymmetry in the interactions of intracellular protozoan parasites with the target and immune cells of the host are highlighted. The malaria parasite Plasmodium infects red blood cells and extensively refurbishes these terminally differentiated cells. Cholesterol depletion and an altered intracellular calcium ion homeostasis can lead to disruption in erythrocyte membrane asymmetry and increased exposure of phosphatidylserine (PS). Binding to the PS receptor on monocytes and macrophages results in phagocytosis and destruction of infected erythrocytes. Leishmania parasites display apoptotic mimicry by actively enhancing PS exposure on their surface to trigger increased infection of macrophages. In extracellular Toxoplasma gondii a P4-type ATPase/CDC50 co-chaperone pair functions as a flippase important for exocytosis of specialised secretory organelles. Identification and functional analysis of parasite lipid-translocating proteins, i.e. flippases, floppases, and scramblases, will be central for the recognition of the molecular mechanisms of parasite/host interactions. Ultimately, a better understanding of parasitic diseases, host immunity, and immune escape by parasites require more research on the dynamics of phospholipid bilayers of parasites and the infected host cell.


Assuntos
Parasitos , Toxoplasma , Animais , Interações Hospedeiro-Parasita , Fosfolipídeos/metabolismo , Toxoplasma/metabolismo , Eucariotos/metabolismo
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