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Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance

Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasit...

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Autores principales: Lin, Jing-wen, Spaccapelo, Roberta, Schwarzer, Evelin, Sajid, Mohammed, Annoura, Takeshi, Deroost, Katrien, Ravelli, Raimond B.G., Aime, Elena, Capuccini, Barbara, Mommaas-Kienhuis, Anna M., O’Toole, Tom, Prins, Frans, Franke-Fayard, Blandine M.D., Ramesar, Jai, Chevalley-Maurel, Séverine, Kroeze, Hans, Koster, Abraham J., Tanke, Hans J., Crisanti, Andrea, Langhorne, Jean, Arese, Paolo, Van den Steen, Philippe E., Janse, Chris J., Khan, Shahid M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451122/
https://www.ncbi.nlm.nih.gov/pubmed/25941254
http://dx.doi.org/10.1084/jem.20141731
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author Lin, Jing-wen
Spaccapelo, Roberta
Schwarzer, Evelin
Sajid, Mohammed
Annoura, Takeshi
Deroost, Katrien
Ravelli, Raimond B.G.
Aime, Elena
Capuccini, Barbara
Mommaas-Kienhuis, Anna M.
O’Toole, Tom
Prins, Frans
Franke-Fayard, Blandine M.D.
Ramesar, Jai
Chevalley-Maurel, Séverine
Kroeze, Hans
Koster, Abraham J.
Tanke, Hans J.
Crisanti, Andrea
Langhorne, Jean
Arese, Paolo
Van den Steen, Philippe E.
Janse, Chris J.
Khan, Shahid M.
author_facet Lin, Jing-wen
Spaccapelo, Roberta
Schwarzer, Evelin
Sajid, Mohammed
Annoura, Takeshi
Deroost, Katrien
Ravelli, Raimond B.G.
Aime, Elena
Capuccini, Barbara
Mommaas-Kienhuis, Anna M.
O’Toole, Tom
Prins, Frans
Franke-Fayard, Blandine M.D.
Ramesar, Jai
Chevalley-Maurel, Séverine
Kroeze, Hans
Koster, Abraham J.
Tanke, Hans J.
Crisanti, Andrea
Langhorne, Jean
Arese, Paolo
Van den Steen, Philippe E.
Janse, Chris J.
Khan, Shahid M.
author_sort Lin, Jing-wen
collection PubMed
description Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes.
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spelling pubmed-44511222015-12-01 Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance Lin, Jing-wen Spaccapelo, Roberta Schwarzer, Evelin Sajid, Mohammed Annoura, Takeshi Deroost, Katrien Ravelli, Raimond B.G. Aime, Elena Capuccini, Barbara Mommaas-Kienhuis, Anna M. O’Toole, Tom Prins, Frans Franke-Fayard, Blandine M.D. Ramesar, Jai Chevalley-Maurel, Séverine Kroeze, Hans Koster, Abraham J. Tanke, Hans J. Crisanti, Andrea Langhorne, Jean Arese, Paolo Van den Steen, Philippe E. Janse, Chris J. Khan, Shahid M. J Exp Med Brief Definitive Report Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes. The Rockefeller University Press 2015-06-01 /pmc/articles/PMC4451122/ /pubmed/25941254 http://dx.doi.org/10.1084/jem.20141731 Text en © 2015 Lin et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Lin, Jing-wen
Spaccapelo, Roberta
Schwarzer, Evelin
Sajid, Mohammed
Annoura, Takeshi
Deroost, Katrien
Ravelli, Raimond B.G.
Aime, Elena
Capuccini, Barbara
Mommaas-Kienhuis, Anna M.
O’Toole, Tom
Prins, Frans
Franke-Fayard, Blandine M.D.
Ramesar, Jai
Chevalley-Maurel, Séverine
Kroeze, Hans
Koster, Abraham J.
Tanke, Hans J.
Crisanti, Andrea
Langhorne, Jean
Arese, Paolo
Van den Steen, Philippe E.
Janse, Chris J.
Khan, Shahid M.
Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title_full Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title_fullStr Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title_full_unstemmed Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title_short Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
title_sort replication of plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451122/
https://www.ncbi.nlm.nih.gov/pubmed/25941254
http://dx.doi.org/10.1084/jem.20141731
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