Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria

Frank P. Mockenhaupt, Jakob P. Cramer, Lutz Hamann, Miriam S. Stegemann, Jana Eckert, Na Ri Oh, Rowland N. Otchwemah, Ekkehart Dietz, Stephan Ehrhardt, Nicolas W.J. Schröder, Ulrich Bienzle, Ralf R. Schumann

Research output: Contribution to journalArticlepeer-review

Abstract

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 glycosylphosphatidylinositol anchor induces signaling in host cells via TLR-2 and -4, whereas hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of proinflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response in malaria, including cytokine induction and 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 rare previously undescribed mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9 Toll/IL-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 1.5- and 2.6-fold increased risks of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation.

Original languageEnglish (US)
Pages (from-to)177-182
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number1
DOIs
StatePublished - Jan 3 2006
Externally publishedYes

Keywords

  • Innate immunity
  • Plasmodium falciparum
  • Single-nucleotide polymorphisms

ASJC Scopus subject areas

  • General

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