Samples were …DiscussionPatients suffering from infections done seem to react individually to a similar insult. This capability to combat an infection is thought to be at least in part influenced by genetic factors [23]. Despite important advances in the understanding of the pathophysiological processes leading to sepsis and septic shock [4,24,25], knowledge on the role of genetic factors contributing to sepsis susceptibility has not yet translated into improved outcome [26,27].In the first part of this study we were able to show an association between the risk of severe infections and a combination of genetic variants in sequential molecules of the LPS-sensor consisting of TLR4 and its adaptor TIRAP/Mal.

The presence of TLR4 mutations in combination with TIRAP/Mal variants – either homozygous or heterozygous – resulted in a statistically significant increase in the risk of severe infections. Despite the fact that the number of patients carrying these mutations is low, we found intriguingly low serum levels of pro-inflammatory cytokines in double-mutant individuals in a second cohort (Group II). Additionally we found that monocytes of these patients show decreased cytokine production upon stimulation with LPS. One might speculate that moderate defects in TLR4 and TIRAP/Mal function may accumulate to induce significant alterations of TLR4 dependent signals. However, clinical outcome data in this cohort could not support the findings with regard to sepsis severity. One reason for this discrepancy could be that the second cohort consisted of more severely ill patients already suffering from infections caused by highly resistant Gram-negative pathogens.

Moreover, other confounding factors may influence those effects such as preexisting conditions, type of infection in surgical patients or causing microrganisms. As the innate immune response to bacterial infection has to be mounted early and effectively, genetic influence on cytokine response in infection may determine effectiveness of bacterial killing [28].Supporting our results, it has been recently found that severe sepsis and septic shock is associated with decreased expression of TLR4 on host immune cells [29]. Thus, a lack in TLR4 signaling may be associated with a worse outcome of disease, which also correlates Dacomitinib with the recent findings suggesting that immunosuppression caused by negative regulators of TLR signaling are associated with sepsis mortality [30].To further differentiate whether the observed lack in inducibility of cytokines depended on the type of inflammation, either bacterial infection or sterile inflammatory stimulus, we also assessed postoperative cytokine response following cardiac surgery (Group III).