Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.
Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.
Mockenhaupt
F P
FP
Institute of Tropical Medicine Berlin, Charité-Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin, Germany.
Cramer
J P
JP
Hamann
L
L
Stegemann
M S
MS
Eckert
J
J
Oh
Na-Ri
NR
Otchwemah
R N
RN
Dietz
E
E
Ehrhardt
S
S
Schröder
N W J
NW
Bienzle
U
U
Schumann
R R
RR
D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005869:Ghana; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007223:Infant; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9