Jo-Anne Chan1, Michelle J Boyle1, Kerryn A Moore1,2,3, Linda Reiling1, Zaw Lin1, Wina Hasang4, Marion Avril5, Laurens Manning6,7, Ivo Mueller8, Moses Laman6, Timothy Davis7, Joseph D Smith5, Stephen J Rogerson4, Julie A Simpson2, Freya J I Fowkes1,2,9,10, James G Beeson1,4,11. 1. Burnet Institute for Medical Research and Public Health, Melbourne. 2. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville. 3. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne. 4. Department of Medicine, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Australia. 5. Center for Infectious Diseases Research, Seattle, Washington. 6. Papua New Guinea Institute of Medical Research, Madang. 7. University of Western Australia, Perth. 8. Walter and Eliza Hall Institute of Medical Research, Parkville. 9. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. 10. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia. 11. Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
Abstract
BACKGROUND: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited. METHODS: Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity. RESULTS: Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria. CONCLUSIONS: Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.
BACKGROUND: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited. METHODS: Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity. RESULTS: Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria. CONCLUSIONS: Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.
Authors: G D Turner; H Morrison; M Jones; T M Davis; S Looareesuwan; I D Buley; K C Gatter; C I Newbold; S Pukritayakamee; B Nagachinta Journal: Am J Pathol Date: 1994-11 Impact factor: 4.307
Authors: Antoine Claessens; Yvonne Adams; Ashfaq Ghumra; Gabriella Lindergard; Caitlin C Buchan; Cheryl Andisi; Peter C Bull; Sachel Mok; Archna P Gupta; Christian W Wang; Louise Turner; Mònica Arman; Ahmed Raza; Zbynek Bozdech; J Alexandra Rowe Journal: Proc Natl Acad Sci U S A Date: 2012-05-22 Impact factor: 11.205
Authors: Ricardo Ataíde; Wina Hasang; Danny W Wilson; James G Beeson; Victor Mwapasa; Malcolm E Molyneux; Steven R Meshnick; Stephen J Rogerson Journal: PLoS One Date: 2010-05-25 Impact factor: 3.240
Authors: Sandra K Nilsson Bark; Rushdy Ahmad; Kathleen Dantzler; Amanda K Lukens; Mariana De Niz; Matthew J Szucs; Xiaoying Jin; Joanne Cotton; Dietmar Hoffmann; Eva Bric-Furlong; Ray Oomen; Mark Parrington; Dan Milner; Daniel E Neafsey; Steven A Carr; Dyann F Wirth; Matthias Marti Journal: Mol Cell Proteomics Date: 2017-11-21 Impact factor: 5.911
Authors: Jakob S Jespersen; Christian W Wang; Sixbert I Mkumbaye; Daniel Tr Minja; Bent Petersen; Louise Turner; Jens Ev Petersen; John Pa Lusingu; Thor G Theander; Thomas Lavstsen Journal: EMBO Mol Med Date: 2016-08-01 Impact factor: 12.137
Authors: Mark A Travassos; Amadou Niangaly; Jason A Bailey; Amed Ouattara; Drissa Coulibaly; Kirsten E Lyke; Matthew B Laurens; Jozelyn Pablo; Algis Jasinskas; Rie Nakajima; Andrea A Berry; Matthew Adams; Christopher G Jacob; Andrew Pike; Shannon Takala-Harrison; Li Liang; Bourema Kouriba; Abdoulaye K Kone; J Alexandra Rowe; JoAnn Moulds; Dapa A Diallo; Ogobara K Doumbo; Mahamadou A Thera; Philip L Felgner; Christopher V Plowe Journal: Sci Rep Date: 2018-04-19 Impact factor: 4.379
Authors: Clinton K Y Lau; Louise Turner; Jakob S Jespersen; Edward D Lowe; Bent Petersen; Christian W Wang; Jens E V Petersen; John Lusingu; Thor G Theander; Thomas Lavstsen; Matthew K Higgins Journal: Cell Host Microbe Date: 2014-12-04 Impact factor: 21.023
Authors: Fauzia K Musasia; Irene N Nkumama; Roland Frank; Victor Kipkemboi; Martin Schneider; Kennedy Mwai; Dennis O Odera; Micha Rosenkranz; Kristin Fürle; Domitila Kimani; James Tuju; Patricia Njuguna; Mainga Hamaluba; Melissa C Kapulu; Hedda Wardemann; Faith H A Osier Journal: Nat Commun Date: 2022-07-14 Impact factor: 17.694
Authors: Janavi S Rambhatla; Gerry Q Tonkin-Hill; Eizo Takashima; Takafumi Tsuboi; Rintis Noviyanti; Leily Trianty; Boni F Sebayang; Daniel A Lampah; Jutta Marfurt; Ric N Price; Nicholas M Anstey; Anthony T Papenfuss; Timon Damelang; Amy W Chung; Michael F Duffy; Stephen J Rogerson Journal: Infect Immun Date: 2021-12-06 Impact factor: 3.609
Authors: Andriy Derkach; Isaac Otim; Ruth M Pfeiffer; Olusegun O Onabajo; Ismail D Legason; Hadijah Nabalende; Martin D Ogwang; Patrick Kerchan; Ambrose O Talisuna; Leona W Ayers; Steven J Reynolds; Francis Nkrumah; Janet Neequaye; Kishor Bhatia; Thor G Theander; Ludmila Prokunina-Olsson; Louise Turner; James J Goedert; Thomas Lavstsen; Sam M Mbulaiteye Journal: EBioMedicine Date: 2018-12-20 Impact factor: 8.143
Authors: Rebecca W Olsen; Gertrude Ecklu-Mensah; Anja Bengtsson; Michael F Ofori; Kwadwo A Kusi; Kwadwo A Koram; Lars Hviid; Yvonne Adams; Anja T R Jensen Journal: Infect Immun Date: 2019-09-19 Impact factor: 3.441
Authors: Bernard N Kanoi; Hikaru Nagaoka; Michael T White; Masayuki Morita; Nirianne M Q Palacpac; Edward H Ntege; Betty Balikagala; Adoke Yeka; Thomas G Egwang; Toshihiro Horii; Takafumi Tsuboi; Eizo Takashima Journal: Front Immunol Date: 2020-05-12 Impact factor: 7.561
Authors: Liriye Kurtovic; Michelle J Boyle; D Herbert Opi; Alexander T Kennedy; Wai-Hong Tham; Linda Reiling; Jo-Anne Chan; James G Beeson Journal: Immunol Rev Date: 2019-09-26 Impact factor: 12.988
Authors: Brittany N Araj; Bruce Swihart; Robert Morrison; Patricia Gonzales Hurtado; Andrew Teo; Almahamoudou Mahamar; Oumar Attaher; Bacary S Diarra; Santara Gaoussou; Djibrilla Issiaka; Alassane Dicko; Patrick E Duffy; Michal Fried Journal: mSystems Date: 2021-06-15 Impact factor: 6.496
Authors: S Jake Gonzales; Raphael A Reyes; Ashley E Braddom; Gayani Batugedara; Sebastiaan Bol; Evelien M Bunnik Journal: Front Immunol Date: 2020-10-29 Impact factor: 7.561