In the model for S. pneumoniae-induced pneumonia, we observed an unexpected detrimental role for CD14 in the innate host defense response. S. pneumoniae, a Gram-positive bacterium and the single most frequent pathogen causing community-acquired pneumonia, induces severe lung infl ammation and sepsis in wild-type mice after intranasal instillation. Strikingly, CD14defi cient mice were protected against pneumococcal pneumonia, presumably as a result of reduced bacterial spread to the circulation and reduced lung infl ammation [41] . In contrast, TLR2-defi cient and TLR4-mutant mice were not protected against pneumococcal pneumonia [38, 42] , but in fact TLR2 seemed redundant for effi cient bacterial clearance and TLR4-mutant mice were more susceptible to pneumonia, accompanied by impaired bacterial clearance. However, as in CD14-defi cient mice, lung infl ammation was also reduced in pneumococciinfected TLR2-defi cient mice [42] . Since intrapulmonary treatment with sCD14 rendered CD14-defi cient mice equally susceptible to S. pneumoniae as wild-type mice [41] , these results suggest that S. pneumoniae abuses (s) CD14 in the lung to cause invasive respiratory tract infection. Interestingly, the phenotype of CD14 defi cient mice strongly resembled the phenotype of mice defi cient for PAFR [43] , a receptor for phosphoryl choline from the pneumococcal cell wall which facilitates pneumococcal invasion of cells. Further studies are required to determine whether CD14 serves as a chaperone in the presentation of S. pneumoniae to the PAFR so that the phosphoryl-PAFR-mediated invasion is facilitated.