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

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 TLR͞IL-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 Toll͞IL-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.single-nucleotide polymorphisms ͉ innate immunity ͉ Plasmodium falciparum

Polymorphisms of toll-like receptor 2 and 4 genes in Chagas disease

“…Significant differences in allele frequencies have been reported between ethnically diverse populations. The TLR2 Arg753Gln polymorphism which is absent in our population, is similar to that observed in a case-control study among Ghanaian children (Mockenhaupt et al 2006). In European populations the frequency varies between 6-14% (Folwaczny et al 2004, Lorenz et al 2001.…”

“…A very low frequency of these polymorphisms was observed in our study population, 2.6% for Asp299Gly and 1.8% for Thr399Ile compared with similar studies in Spanish and German populations (Schroder et al 2003, Sánchez et al 2004). These polymorphisms have been observed associated with severe malaria (Mockenhaupt et al 2006) and Gram-negative infection (Genc et al 2004). In T. cruzi infection, both in vitro and knockout mice studies, have shown that innate immunity plays a crucial role in resistance to infection, as well as in parasite-induced cytokine response, TLR4-mutant mice were susceptible to T. cruzi infection with higher parasitemia showing earlier mortality , Oliveira et al 2004).…”

“…The TLR2 argin-ine to glutamine substitution at residue 753 (Arg753Gln) have been described to increase the risk of tuberculosis (Ogus et al 2004, Ben-Ali et al 2004). For TLR4, two frequently co-segregating polymorphisms (Asp299Gly-Thr399Ile) are at increased risk of septic shock (Lorenz et al 2002), Gram-negative infection (Genc et al 2004) and, severe malaria (Mockenhaupt et al 2006).…”

Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

“…Gram-negative infection 31 or septic shock due to Gram-negative organisms, 32 severe malaria, 33 brucellosis, 34 Crohn's disease 35 and severe sepsis following burn injury. 36 On the other hand, the same alleles have shown protective effects against various diseases such as atherosclerosis, 37 Legionnaire's disease 38 and late-onset Alzheimer's disease.…”

Polymorphisms in Toll-like receptor genes and risk of cancer

“…SNP Asp299Gly was later shown to co-segregate with SNP Thr399Ile-also in the third exon of TLR4. Both SNPs are present in 10% of Caucasian populations and are reported to have a positive correlation with susceptibility to several infectious diseases (including gram-negative sepsis), atherosclerosis, asthma, malaria and also Helicobacter pylori-induced gastric cancer and its precursors (Mockenhaupt et al, 2006;Hold et al, 2007). However, neither SNP is present in Asian populations.…”