ALBERT

Description: Cysteine proteases of Plasmodium falciparum are required for survival of the malaria parasite, yet their specific cellular functions remain unclear. We used a chemical proteomic screen with a small-molecule probe to characterize the predominant cysteine proteases throughout the parasite life cycle. Only one protease, falcipain 1, was active during the invasive merozoite stage. Falcipain 1-specific inhibitors, identified by screening of chemical libraries, blocked parasite invasion of host erythrocytes, yet had no effect on normal parasite processes such as hemoglobin degradation. These results demonstrate a specific role for falcipain 1 in host cell invasion and establish a potential new target for antimalarial therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greenbaum, Doron C -- Baruch, Amos -- Grainger, Munira -- Bozdech, Zbynek -- Medzihradszky, Katlin F -- Engel, Juan -- DeRisi, Joseph -- Holder, Anthony A -- Bogyo, Matthew -- MC_U117532067/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2002 Dec 6;298(5600):2002-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA. dgreenb@itsa.ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12471262" target="_blank"〉PubMed〈/a〉

Description: Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mok, Sachel -- Ashley, Elizabeth A -- Ferreira, Pedro E -- Zhu, Lei -- Lin, Zhaoting -- Yeo, Tomas -- Chotivanich, Kesinee -- Imwong, Mallika -- Pukrittayakamee, Sasithon -- Dhorda, Mehul -- Nguon, Chea -- Lim, Pharath -- Amaratunga, Chanaki -- Suon, Seila -- Hien, Tran Tinh -- Htut, Ye -- Faiz, M Abul -- Onyamboko, Marie A -- Mayxay, Mayfong -- Newton, Paul N -- Tripura, Rupam -- Woodrow, Charles J -- Miotto, Olivo -- Kwiatkowski, Dominic P -- Nosten, Francois -- Day, Nicholas P J -- Preiser, Peter R -- White, Nicholas J -- Dondorp, Arjen M -- Fairhurst, Rick M -- Bozdech, Zbynek -- 089276/Wellcome Trust/United Kingdom -- 090770/Wellcome Trust/United Kingdom -- 093956/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):431-5. doi: 10.1126/science.1260403. Epub 2014 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, Nanyang Technological University, Singapore. ; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ; Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. ; Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. ; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. WorldWide Antimalarial Resistance Network (WWARN), Asia Regional Centre, Mahidol University, Bangkok, Thailand. WorldWide Antimalarial Resistance Network, University of Maryland School of Medicine, Baltimore, MD, USA. ; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. ; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Oxford University Clinical Research Unit (OUCRU), Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. ; Department of Medical Research, Lower Myanmar, Yangon, Myanmar. ; Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh. ; Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo. ; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR. Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR. ; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR. ; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. ; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. ; Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. ; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand. ; School of Biological Sciences, Nanyang Technological University, Singapore. zbozdech@ntu.edu.sg.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25502316" target="_blank"〉PubMed〈/a〉

Description: Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11- to 〉100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann–Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann–Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.