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Objective As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression. Design Therefore, the TLR9 SNPs and the interferon lambda 4 ( IFNL4 ) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) ‘anti-D’ cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers. Results The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both ‘anti-D’ cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women. Conclusions TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.

Severe sepsis and septic shock are important causes of death in intensive care units. Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated into clinical benefit. Several new treatment approaches have given encouraging results. Evidence suggests that the way forward is to develop pathogen specific regimens rather than assume that one treatment fits all. #### Summary points Bacterial cell walls, endotoxins, and exotoxins are powerful activators of innate and acquired immune responses Molecules expressed by pathogens interact with Toll-like receptors on immune cells, activating the immune response Cytokines are important in the pathogenesis of sepsis Susceptibility to sepsis may be due to inherited or acquired mutations of innate immune genes Severe sepsis and septic shock are clinical manifestations of a dysregulated immune response to invasive pathogens Adjunctive therapy with low dose steroids, activated protein C or early supportive care can reduce mortality from severe sepsis and septic shock Pathogen recognition receptors (such as Toll-like receptors) and mediators of sepsis (such as macrophage migration inhibitory factor) might be novel targets for treatment We selected articles for this review by searching Medline using the keywords sepsis, therapy, and Toll-like receptors. We concentrated on publications on the pathogenesis of sepsis and treatment of septic shock. As the number of references that could be cited was limited, we have often referenced review articles rather than original publications. Severe sepsis and septic shock are life threatening complications of infections and the most common cause of death in intensive care units. However, a lack of widely accepted definitions of these complications has made it difficult to obtain accurate estimates of their frequency. A study published by the Centers for Disease Control in the United States indicated that the incidence of septicaemia had increased from 73.6 per 100 000 patients in …

We read with interest the paper by Hayes et al 1 on the impact of genetic polymorphisms near IL28B in predicting treatment response in chronic hepatitis C patients infected with hepatitis C virus genotype 1 (HCV-1). These results confirm the large, existing evidence in support of single nucleotide polymorphisms (SNPs) near IL28B being the most powerful predictors of virological response in patients infected with all major HCV genotypes, that is, 1–4.2 No data is available for HCV-5, a rare genotype neglected in clinical trials.3 We report IL28B SNP frequency and its impact on treatment outcome in 49 patients of homogeneous Caucasian ancestry, all from Syria, infected with HCV-5. Treatment included 180 μg …