The Role of Lipopolysaccharide Binding Protein in Resistance to Salmonella Infections in Mice

Abstract

Polymorphonuclear leukocytes (PMN) and LPS-binding protein (LBP) are both components of the innate immune system. LBP is a plasma protein that binds to lipid A and enhances the biological activity of LPS 100- to 1000-fold. Recently it was reported that LBP-deficient mice are more susceptible to Salmonella typhimurium infection. Here we report that LBP KO mice are more susceptible to Salmonella peritonitis, but not to oral or i.v. infection. LBP knockout (KO) mice responded normally to i.p. injections of Staphylococcus aureus and casein, but not to i.p. injection of S. typhimurium or Salmonella LPS. Mice with a mutation in Toll-like receptor 4 (C3H/HeJ) have a similar defect in PMN chemotaxis. In normal mice S. typhimurium stimulated production of the CXC chemokines macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant, but levels of cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein-2 were greatly reduced in the LBP KO mice. LBP KO mice pretreated with casein to attract PMN in an LBP-independent manner were more resistant to Salmonella infection, but neutropenic mice were not protected by casein. Splenic TNF-α mRNA levels were also lower in LBP KO than in control mice infected with Salmonella. Since TNF-α can activate PMN, LBP KO mice may have both fewer and less active PMN in the first few hours after Salmonella are injected, making LBP KO mice more susceptible. This work confirms the importance of PMN in resistance to Salmonella infections and shows that this is facilitated by LBP.

Lipopolysaccharide Binding Protein Is an Essential Component of the Innate Immune Response toEscherichia coliPeritonitis in Mice

“…The biological significance of LBP was established when LBP gene-deficient (LBP Ϫ/Ϫ ) mice were shown to be resistant to LPS toxicity and highly susceptible to Salmonella enterica serovar Typhimurium peritonitis (5,11). Similar observations for Salmonella peritonitis were made with mice lacking CD14 or TLR4, emphasizing the importance of these three components of the LPS recognition machinery in this gram-negative infection (1).…”

Innate immune response to intramammary infection with Serratia marcescens and Streptococcus uberis

“…LBP is a hepatically-derived acute phase protein that enhances CD14/TLR recognition of bacterial cell wall products [49]. An array of experimental approaches, including the use of LBP -/- [14,20] or CD14 -/- [65] mice, CD14 neutralizing antibodies [25,63], and administration of exogenous LBP [24] have established a protective role for CD14 and LBP in mediating host responses to LPS and Gram-negative bacterial infection. We have shown that exogenous recombinant bovine sCD14 enhances intramammary clearance of E. coli in both mice [26] and cattle [27].…”

Evidence of a bactericidal permeability increasing protein in an invertebrate, theCrassostrea gigas Cg-BPI

“…Originally, hBPI has been shown to be expressed in neutrophils (8), which are mobilized during an acute response to tissue sites of bacterial invasion (32). However, further studies have shown that hBPI is expressed in various mucosal epithelia where it can be up-regulated in response to aspirin-triggered antiinflammatory lipids (lipoxins) (33).…”