The ability to develop knock-out mice deficient in specific components of TLR signaling has emphasized the important role of TLRs in infection control. For example, TLR-2–deficient mice have been shown to be susceptible to Staphylococcus aureus,12 pneumococcal,27and mycobacterial infections; TLR-4–deficient mice are susceptible to Gram-negative infections28–; and TLR-3–deficient mice are susceptible to viruses such as cytomegalovirus.29Completely nonfunctional variants are extremely rare in humans, presumably as they would carry little chance of survival of individuals to reproductive age. Recently, however, individuals have been identified with recurrent life-threatening bacterial infections who have mutations in IL-receptor–associated kinase 4, a key component of TLR and IL-1 signaling pathways.30–31 Several studies have begun to examine the impact of TLR deficiency (ie, knock-out mice) on survival in pneumonia models. Such studies33 are generating data that clearly indicate a role for TLRs in the inflammatory response to microbes; although depending on the microbe and model, contributions of individual TLRs to bacterial clearance are still variable. Archer and Roy34showed a role for TLR-2 in responses to Legionella pneumophila, and TLR-2 and TLR-4 both seem important in responses to Chlamydia pneumoniae.35 Gene deficiencies do not always correlate with impaired microbe clearance, as illustrated by a study36showing no effect of TLR-2 deficiency on survival in response to pneumococcal infections, although TLR-4 deficiency prevents recognition of pneumococcal pneumolysin, and does convey increased risk of death from pneumonia in mouse models.37 TLR-5 also contributes importantly to responses to bacteria such as Pseudomonas aeruginosa.,32,38 These data make it clear that, in man, microbial recognition, and probably effective clearance, will heavily involve TLR-mediated recognition.