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

F. P. Mockenhaupt, J. P. Cramer, L. Hamann, M. S. Stegemann, J. Eckert, Na Ri Oh, R. N. Otchwemah, E. Dietz, S. Ehrhardt, N. W.J. Schröder, U. Bienzle, R. R. Schumann

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)230-245
Number of pages16
JournalJournal of Communicable Diseases
Volume38
Issue number3
StatePublished - Mar 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Infectious Diseases

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    Mockenhaupt, F. P., Cramer, J. P., Hamann, L., Stegemann, M. S., Eckert, J., Oh, N. R., Otchwemah, R. N., Dietz, E., Ehrhardt, S., Schröder, N. W. J., Bienzle, U., & Schumann, R. R. (2006). Toll-Like Receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Journal of Communicable Diseases, 38(3), 230-245.