Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children.
BACKGROUND
Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein interactions that mediate invasion are still poorly understood, the P. vivax Reticulocyte-Binding Protein family (PvRBP) is thought to be involved in P. vivax restricted host-cell selectivity.


RESULTS
We assessed the binding specificity of five members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, PvRBP2-P2 and a non-binding fragment of PvRBP2c) to normocytes or reticulocytes. PvRBP2b was identified as the only reticulocyte-specific binder (P<0.001), whereas the others preferentially bound to normocytes (PvRBP1a/b P≤0.034), or showed comparable binding to both (PvRBP2a/2-P2, P = 0.38). Furthermore, we measured levels of total and IgG subclasses 1, 2, 3 and 4 to the six PvRBPs in a cohort of young Papua New Guinean children, and assessed their relationship with prospective risk of P. vivax malaria. Children had substantial, highly correlated (rho = 0.49-0.82, P<0.001) antibody levels to all six PvRBPs, with dominant IgG1 and IgG3 subclasses. Both total IgG (Incidence Rate Ratio [IRR] 0.63-0.73, P = 0.008-0.041) and IgG1 (IRR 0.56-0.69, P = 0.001-0.035) to PvRBP2b and PvRBP1a were strongly associated with reduced risk of vivax-malaria, independently of age and exposure.


CONCLUSIONS
These results demonstrate a diversity of erythrocyte-binding phenotypes of PvRBPs, indicating binding to both reticulocyte-specific and normocyte-specific ligands. Our findings provide further insights into the naturally acquired immunity to P. vivax and highlight the importance of PvRBP proteins as targets of naturally acquired humoral immunity. In-depth studies of the role of PvRBPs in P. vivax invasion and functional validation of the role of anti-PvRBP antibodies in clinical immunity against P. vivax are now required to confirm the potential of the reticulocyte-binding PvRBP2b and PvRBP1a as vaccine candidate antigens.
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
Camila T
CT
França
Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Wen-Qiang
WQ
He
Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Jakub
J
Gruszczyk
Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Nicholas T Y
NT
Lim
Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Madang, Papua New Guinea.
Enmoore
E
Lin
Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Madang, Papua New Guinea.
Benson
B
Kiniboro
Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Madang, Papua New Guinea.
Peter M
PM
Siba
Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Wai-Hong
WH
Tham
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Malaria Parasites and Hosts Unit, Department of Parasites and Insect Vectors, Pasteur Institute, Paris, France.|Barcelona Institute of Global Health (ISGLOBAL), Barcelona, Spain.
Ivo
http://orcid.org/0000-0001-6554-6889
I
Mueller
Trans R Soc Trop Med Hyg. 2013 May;107(5):328-31
23584375
PLoS One. 2012;7(3):e32105
22403626
J Immunol. 2010 Nov 15;185(10):6157-67
20962255
Cell. 1992 Jun 26;69(7):1213-26
1617731
Infect Immun. 2015 Feb;83(2):646-60
25422270
J Infect Dis. 2008 Jul 1;198(1):134-42
18471084
J Med Virol. 2009 Jun;81(6):1088-93
19382256
PLoS Pathog. 2015 Dec 22;11(12):e1005343
26694741
Malar J. 2014 Nov 05;13:425
25373511
BMC Med. 2014 Jul 01;12:108
24980799
Parasitology. 2016 Feb;143(2):154-70
26864134
Nat Commun. 2011 Dec 20;2:601
22186897
Acta Trop. 2015 Feb;142:47-56
25446174
Front Immunol. 2014 Oct 20;5:520
25368619
Pharmacol Ther. 2002 Jul;95(1):21-45
12163126
Nature. 2014 Nov 20;515(7527):427-30
25132548
PLoS Negl Trop Dis. 2013 Nov 14;7(11):e2498
24244763
Elife. 2014 Oct 08;3:null
25296023
Vaccine. 2007 May 4;25(18):3713-21
17240494
PLoS Pathog. 2015 Feb 27;11(2):e1004670
25723550
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5967-71
20231434
Vaccine. 2013 Jan 2;31(2):373-9
23146673
Korean J Parasitol. 2015 Aug;53(4):403-11
26323838
Clin Infect Dis. 2010 Oct 15;51(8):e50-60
20843207
PLoS Negl Trop Dis. 2016 May 16;10(5):e0004639
27182597
Cell Host Microbe. 2015 Jan 14;17(1):130-9
25590760
Infect Immun. 2015 Dec 28;84(3):677-85
26712206
Vaccine. 2015 Dec 22;33(52):7433-43
26458807
Trends Parasitol. 2012 Jan;28(1):23-30
22178537
Blood. 1994 Jul 1;84(1):44-52
7517217
BMC Med. 2014 Sep 09;12:150
25199532
PLoS One. 2011;6(11):e28126
22140521
Am J Trop Med Hyg. 2008 May;78(5):729-32
18458304
Infect Immun. 2006 Jan;74(1):257-64
16368979
PLoS Negl Trop Dis. 2013 Dec 05;7(12):e2569
24340114
Infect Immun. 2000 Mar;68(3):1252-8
10678934
Lancet Infect Dis. 2009 Sep;9(9):555-66
19695492
Am J Trop Med Hyg. 2005 Jun;72(6):666-74
15964948
PLoS Negl Trop Dis. 2013 Sep 05;7(9):e2403
24040428
Am J Trop Med Hyg. 2005 Aug;73(2):244-55
16103583
Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17327-32
20855594
Nature. 2011 Nov 09;480(7378):534-7
22080952
Cytometry. 2001 Sep 1;45(1):27-36
11598944
Vaccine. 2015 Dec 22;33(52):7489-95
26428453
Nature. 2008 Oct 9;455(7214):757-63
18843361
Biochem J. 2013 Jun 15;452(3):457-66
23544851
J Cell Biol. 2012 Sep 17;198(6):961-71
22986493
PLoS One. 2010 Feb 04;5(2):e9047
20140220
Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E191-200
26715754
J Immunol. 2014 Jan 1;192(1):245-58
24293631