ABSTRACTSevere bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by someEscherichia colistrains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurringE. coli, the responses of CD14−/−and CD14+/+mice to three different isolates ofE. coliobtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14−/−mice were resistant to the lethal effects of the K1-negative isolates. This resistance was accompanied by significantly lower levels of systemic tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in these mice than in CD14+/+mice, enhanced clearance of the bacteria, and significantly fewer additional gross symptoms. In contrast, CD14−/−mice were as sensitive as CD14+/+mice to the lethal effects of the K1-positive isolates, even though they had significantly lower levels of TNF-α and IL-6 than CD14+/+mice. These studies show that different bacterial isolates can use distinctly different mechanisms to cause disease and suggest that new, nonantibiotic therapeutics need to be directed against multiple targets.