THE IMPORTANCE OF A LIPOPOLYSACCHARIDE-INITIATED, CYTOKINE-MEDIATED HOST-DEFENSE MECHANISM IN MICE AGAINST EXTRAINTESTINALLY INVASIVE ESCHERICHIA-COLI

Extraintestinally invasive Escherichia coli (EC) that possess both a c omplete LPS and K1 capsule evade both complement-mediated bacteriolysi s and neutrophil-mediated killing. Since C3H/HeJ mice that are hypores ponsive to LPS were uniquely susceptible to lethal infection with EC o f this phenotype, we speculated there was an LPS-initiated host defens e mechanism against this pathogenic phenotype, The LPS-normoresponsive C3H/HeN as well, as the C3H/HeJ mice cleared these EC from the circul ation within 4 h of intravenous administration, Whereas electron micro graphs of the liver demonstrated these EC undergoing degeneration with in the phagolysosomes of of both macrophages and Kupffer cells of C3H/ HeN mice, these EC replicated within these cells of the C3H/HeJ mice, Restoration of anti-EC activity of C3H/HeJ mice occurred with activati on of Kupffer cells and peritoneal macrophages in vivo with BCG and in vitro with IFN-gamma, but not with LPS, Pretreatment of C3H/HeJ mice with a combination of recombinant murine IL-1 and TNF-alpha also resto red the killing of K1(+)-EC but did not enhance the killing of a K1(-) -EC mutant. These data are consistent with the hypothesis that (a) the re is no intrinsic inability of C3H/HeJ phagocytes to kill EC, but (b) an LPS-initiated, cytokine-mediated host defense mechanism is require d for such killing. These studies emphasize the importance of bacteria l surface characteristics in the interaction with specific host defens es.