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Open Access Research

Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study

Jennifer A Greene1, Nadia Sam-Agudu2, Chandy C John2, Robert O Opoka3, Peter A Zimmerman1 and James W Kazura1*

Author Affiliations

1 Case Western Reserve University, Wolstein Research Building, 2103 Cornell Rd, Cleveland, OH 44106, USA

2 University of Minnesota, Minneapolis, MN, USA

3 Makerere University, Kampala, Uganda

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Malaria Journal 2012, 11:47  doi:10.1186/1475-2875-11-47

Published: 15 February 2012

Abstract

Background

In malaria endemic areas, host genetics influence whether a Plasmodium falciparum-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for P. falciparum-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn).

Methods

These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype.

Results

Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007).

Conclusion

Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.

Keywords:
Malaria; Toll-like receptor; Plasmodium falciparum; Polymorphism; GPI