Gene variants of the NLRP3 inflammasome in Staphylococcus aureus-induced severe infection

This project investigates how the host-microbe interplay determines why some individuals respond with severe, life-threatening symptoms upon S. aureus infection, whereas others display a quiescent progression, or are even asymptomatic carriers. The incidence of sepsis and septic shock, which may develop as severe manifestations of bacteraemia, has increased significantly over the last two decades and continuous to be a major cause of morbidity and mortality worldwide. Gram-positive S. aureus is one of the predominating bacteria to cause bacteraemia.

Host genetic factors have been found to play a major role in explaining inter-individual variation in susceptibility to infectious diseases. Q705K in NLRP3 and C10X in CARD8 are two polymorphisms that, per se or combined, have been implicated with increased inflammation, by creating a constitutively assembled inflammasome; resulting in a constant activation of caspase-1 and excessive IL-1β production. The prevalence (5%) suggests these polymorphisms to act as predisposition factors that may, in combination with an exogenous exposure, e.g. infection, elicit an inflammatory response that develops into severe infection.

• Our data most strongly support this idea by showing higher prevalence of C10X polymorphism in patients with bacteraemia; in whom septic symptoms may arise as a rapid consequence of an excessive IL-1β production.
• The present study is designed to establish whether C10X per se or combined with Q705K, also correlates to disease outcome, i.e. survival or death, or solely to susceptibility of severe S. aureus –induced infectious disease.