The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli.

Abstract

Extraintestinally invasive Escherichia coli (EC) that possess both a complete LPS and K1 capsule evade both complement-mediated bacteriolysis and neutrophil-mediated killing. Since C3H/HeJ mice that are hyporesponsive to LPS were uniquely susceptible to lethal infection with EC of this phenotype, we speculated there was an LPS-initiated host defense mechanism against this pathogenic phenotype. The LPS-normoresponsive C3H/HeN as well as the C3H/HeJ mice cleared these EC from the circulation within 4 h of intravenous administration. Whereas electron micrographs of the liver demonstrated these EC undergoing degeneration within 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 activation of Kupffer cells and peritoneal macrophages in vivo with BCG and in vitro with IFN-y, but not with LPS. Pretreatment of C3H/ HeJ mice with a combination of recombinant murine IL-1 and TNF-a also restored 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) there is no intrinsic inability of C3H/HeJ phagocytes to kill EC, but (b) an LPS-initiated, cytokine-mediated host defense mechanism is required for such killing. These studies emphasize the importance of bacterial surface characteristics in the interaction with specific host defenses. (J. Clin. Invest. 1995.

Toll-Like Receptor 4 Dependence of Innate and Adaptive Immunity to Salmonella: Importance of the Kupffer Cell Network

“…Because typical bacteria produce more than one of these ligands, some functional redundancy among individual TLRs might be anticipated. However, point mutations in human TLR4 resulting in reduced function are associated with an increased risk of Gram-negative infections (20), and TLR4-deficient mice have enhanced susceptibility to Gram-negative bacteria (5,6), indicating that the presence of other TLRs cannot necessarily compensate for the loss of another. Similarly, the mouse strains used in this study both possess a functional Nramp1/S1c11a1 locus (21), but this important determinant of host resistance to Salmonella is not sufficient to compensate for the loss of TLR4 in the C3H/HeJ mice.…”

“…However, in contrast to the urinary tract model, the present study demonstrates that TLR4 can regulate direct antimicrobial actions in peripheral tissues in addition to promoting the recruitment of inflammatory cells. Both Kupffer cells and hepatocytes have been shown to express TLR4 (23, 24), and TLR4-deficient Kupffer cells have been found to be deficient in their ability to kill ingested E. coli (6), but the mechanisms of TLR4-dependent antimicrobial actions in Kupffer cells and hepatocytes remain to be established.…”

“…Accordingly, C3H/HeJ mice carrying a dominant-negative mutation in the cytoplasmic domain of TLR4 (3) are resistant to LPS-induced shock and death (4). However, despite their endotoxin resistance, TLR4-deficient C3H/HeJ mice have increased mortality following infection with live Gram-negative bacteria such as Salmonella enterica serovar Typhimurium (S. Typhimurium) (5) or Escherichia coli (6), suggesting that LPS/TLR4 signaling is important for the stimulation of protective immune responses.…”

Blockade of CD14 Increases Shigella-Mediated Invasion and Tissue Destruction

“…Two recent studies have documented the importance of LPS-initiated host defense mechanisms in experimental bacterial infections in mice. Cross and co-workers showed that genetically LPS-hyporesponsive mice were 10,000 times more susceptible to lethal infection with a K1-encapsulated E. coli strain than normal, LPS-responsive mice (30). The lower 50% lethal dose in the LPS-hyporesponsive mice was mainly due to poor activation of monocytes/macrophages (30).…”

“…Cross and co-workers showed that genetically LPS-hyporesponsive mice were 10,000 times more susceptible to lethal infection with a K1-encapsulated E. coli strain than normal, LPS-responsive mice (30). The lower 50% lethal dose in the LPS-hyporesponsive mice was mainly due to poor activation of monocytes/macrophages (30). It was recently demonstrated that these LPS-hyporesponsive mice lack the gene for Toll-like receptor 4, a protein capable of transducing LPS signaling (31,32).…”