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

Eczema, across the clinical severity spectrum in infancy, is a strong risk factor for IgE-mediated food allergy. Infants with eczema were six times more likely to have egg allergy and 11 times more likely to have peanut allergy by 12 months than infants without eczema. Our data suggest that a heightened awareness of food allergy risk among healthcare practitioners treating infants with eczema, especially if early onset and severe, is warranted.

Severe infections with Streptococcus pyogenes, an important human pathogen, are associated with massive inflammatory reactions in the human host. Here we show that streptococcal M protein interacts with TLR2 on human peripheral blood monocytes. As a consequence, monocytes express the cytokines IL-6, IL-1beta, and TNF-alpha. This response is significantly increased in the presence of neutrophil-derived heparin-binding protein (HBP), which co-stimulates monocytes by interacting with CD11/CD18. Analysis of tissue biopsies from patients with necrotizing fasciitis revealed recruitment of neutrophils and monocytes to the infectious site, combined with the release of HBP. The results show that M protein, in synergy with HBP, evokes an inflammatory response that may contribute to the profound pathophysiological consequences seen in severe streptococcal infections.

Toll-like receptors (TLRs) are key components of the innate immune system that trigger antimicrobial host defense responses. The aim of the present study was to analyze the effects of probiotic Escherichia coli Nissle strain 1917 in experimental colitis induced in TLR-2 and TLR-4 knockout mice. Colitis was induced in wild-type (wt), TLR-2 knockout, and TLR-4 knockout mice via administration of 5% dextran sodium sulfate (DSS). Mice were treated with either 0.9% NaCl or 10 7 E. coli Nissle 1917 twice daily, followed by the determination of disease activity, mucosal damage, and cytokine secretion. wt and TLR-2 knockout mice exposed to DSS developed acute colitis, whereas TLR-4 knockout mice developed significantly less inflammation. In wt mice, but not TLR-2 or TLR-4 knockout mice, E. coli Nissle 1917 ameliorated colitis and decreased proinflammatory cytokine secretion. In TLR-2 knockout mice a selective reduction of gamma interferon secretion was observed after E. coli Nissle 1917 treatment. In TLR-4 knockout mice, cytokine secretion was almost undetectable and not modulated by E. coli Nissle 1917, indicating that TLR-4 knockout mice do not develop colitis similar to the wt mice. Coculture of E. coli Nissle 1917 and human T cells increased TLR-2 and TLR-4 protein expression in T cells and increased NF-B activity via TLR-2 and TLR-4. In conclusion, our data provide evidence that E. coli Nissle 1917 ameliorates experimental induced colitis in mice via TLR-2-and TLR-4-dependent pathways.

LPS binding protein (LBP) is an acute-phase protein synthesized predominantly in the liver of the mammalian host. It was first described to bind LPS of Gram-negative bacteria and transfer it via a CD14-enhanced mechanism to a receptor complex including TLR-4 and MD-2, initiating a signal transduction cascade leading to the release of proinflammatory cytokines. In recent studies, we found that LBP also mediates cytokine induction caused by compounds derived from Gram-positive bacteria, including lipoteichoic acid and peptidoglycan fragments. Lipoproteins and lipopeptides have repeatedly been shown to act as potent cytokine inducers, interacting with TLR-2, in synergy with TLR-1 or -6. In this study, we show that these compounds also interact with LBP and CD14. We used triacylated lipopeptides, corresponding to lipoproteins of Borrelia burgdorferi, mycobacteria, and Escherichia coli, as well as diacylated lipopeptides, corresponding to, e.g., 2-kDa macrophage activating lipopeptide of Mycoplasma spp. Activation of Chinese hamster ovary cells transfected with TLR-2 by both lipopeptides was enhanced by cotransfection of CD14. Responsiveness of human mononuclear cells to these compounds was greatly enhanced in the presence of human LBP. Binding of lipopeptides to LBP as well as competitive inhibition of this interaction by LPS was demonstrated in a microplate assay. Furthermore, we were able to show that LBP transfers lipopeptides to CD14 on human monocytes using FACS analysis. These results support that LBP is a pattern recognition receptor transferring a variety of bacterial ligands including the two major types of lipopeptides to CD14 present in different receptor complexes.

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This first report of a functional TLR8 variant associated with a different clinical course of an RNA viral disease may have implications for the individual risk assessment of patients infected with HIV and other RNA viruses as well as for future HIV vaccine development.

This is the first report of a functional TLR7 variant to be associated with susceptibility to and a more severe clinical course of HIV-1 disease. These results may have implications for the risk assessment of individual patients as well as for HIV-1 therapy and vaccination strategies in the future.