Global sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: implications for the performance of malaria rapid diagnostic tests.
BACKGROUND
Accurate diagnosis is essential for prompt and appropriate treatment of malaria. While rapid diagnostic tests (RDTs) offer great potential to improve malaria diagnosis, the sensitivity of RDTs has been reported to be highly variable. One possible factor contributing to variable test performance is the diversity of parasite antigens. This is of particular concern for Plasmodium falciparum histidine-rich protein 2 (PfHRP2)-detecting RDTs since PfHRP2 has been reported to be highly variable in isolates of the Asia-Pacific region.


METHODS
The pfhrp2 exon 2 fragment from 458 isolates of P. falciparum collected from 38 countries was amplified and sequenced. For a subset of 80 isolates, the exon 2 fragment of histidine-rich protein 3 (pfhrp3) was also amplified and sequenced. DNA sequence and statistical analysis of the variation observed in these genes was conducted. The potential impact of the pfhrp2 variation on RDT detection rates was examined by analysing the relationship between sequence characteristics of this gene and the results of the WHO product testing of malaria RDTs: Round 1 (2008), for 34 PfHRP2-detecting RDTs.


RESULTS
Sequence analysis revealed extensive variations in the number and arrangement of various repeats encoded by the genes in parasite populations world-wide. However, no statistically robust correlation between gene structure and RDT detection rate for P. falciparum parasites at 200 parasites per microlitre was identified.


CONCLUSIONS
The results suggest that despite extreme sequence variation, diversity of PfHRP2 does not appear to be a major cause of RDT sensitivity variation.
Baker
Joanne
J
Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia. qin.cheng@defence.gov.au.
Ho
Mei-Fong
MF
Pelecanos
Anita
A
Gatton
Michelle
M
Chen
Nanhua
N
Abdullah
Salim
S
Albertini
Audrey
A
Ariey
Frederic
F
Barnwell
John
J
Bell
David
D
Cunningham
Jane
J
Djalle
Djibrine
D
Echeverry
Diego F
DF
Gamboa
Dionicia
D
Hii
Jeffery
J
Kyaw
Myat Phone
MP
Luchavez
Jennifer
J
Membi
Christopher
C
Menard
Didier
D
Murillo
Claribel
C
Nhem
Sina
S
Ogutu
Bernhards
B
Onyor
Pamela
P
Oyibo
Wellington
W
Wang
Shan Qing
SQ
McCarthy
James
J
Cheng
Qin
Q
D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology; D016054:DNA, Protozoan / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007118:Immunoassay / Q000379:methods* / Q000592:standards; D016778:Malaria, Falciparum / Q000175:diagnosis* / Q000235:genetics / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification*; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D011933:Reagent Kits, Diagnostic; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA
D000953:Antigens, Protozoan; D016054:DNA, Protozoan; C514457:HRP-2 antigen, Plasmodium falciparum; D015800:Protozoan Proteins; D011933:Reagent Kits, Diagnostic
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