The Essential Role of Lipopolysaccharide-Binding Protein in Protection of Mice Against a Peritoneal Salmonella Infection Involves the Rapid Induction of an Inflammatory Response

Abstract

Acute and chronic hyperinflammation are of major clinical concern, and many treatment strategies are therefore directed to inactivating parts of the inflammatory system. However, survival depends on responding quickly to pathogen attack, and since the adaptive immune system requires several days to adequately react, we rely initially on a range of innate defenses, many of which operate by activating parts of the inflammatory network. For example, LPS-binding protein (LBP) can transfer the LPS of Gram-negative bacteria to CD14 on the surface of macrophages, and this initiates an inflammatory reaction. However, the importance of this chain of events in infection is unclear. First, the innate system is redundant, and bacteria have many components that may serve as targets for it. Second, LBP can transfer LPS to other acceptors that do not induce inflammation. In this study, we show that innate defense against a lethal peritoneal infection with Salmonella requires a direct proinflammatory involvement of LBP, and that this is a major nonredundant function of LBP in this infection model. This emphasizes that blocking the LBP-initiated inflammatory cascade disables an essential defense pathway. Any anti-inflammatory protection that may be achieved must be balanced against the risks inherent in blinding the innate system to the presence of Gram-negative pathogens.

Neutrophil Influx in Response to a Peritoneal Infection with Salmonella Is Delayed in Lipopolysaccharide-Binding Protein or CD14-Deficient Mice

“…The observation that both CD14-and TLR4-deficient mice are much more susceptible to a Salmonella infection is in line with the notion that this pathway is a necessary component of innate defense against the pathogen (7). Indeed, the requirement for LBP can be entirely replaced by exogenous application of the proinflammatory mediator TNF, suggesting that the essential nonredundant function of the LBP in these mice is to initiate an inflammatory response (9).…”

“…4, LBP Ϫ/Ϫ animals, both at 2 and 4 h after infection, have a small but significant ( p Ͻ 0.05, Mann-Whitney U test) deficiency in their capacity to clear the infection and hold the multiplication of the pathogen in check. Indeed, a substantially increased number of Salmonella are detected in the peritoneum and in peripheral organs of LBP-deficient animals 24 -72 h after infection (6,9). Thus, a delayed influx of neutrophils into the peritoneum might provide an opportunity for the Salmonella to expand and overwhelm the innate defense system.…”

“…LBP-deficient mice carrying the NRAMP-1 R allele derived from strain CBA were as previously described (9). LBP-deficient animals were backcrossed to strain CBA for four backcross generations and LBP ϩ/Ϫ heterozygotes were then crossed inter se.…”

Genetic regulation of host responses to Salmonella infection in mice

“…116 The critical function of Lbp in resistance to infection was confirmed by the rescue of the susceptible Lbp À/À mice with recombinant mouse Lbp supplementation. 117 Cd14 is a glycosylphosphatidylinositol-anchored molecule that is expressed on monocytes and neutrophils and acts as a high-affinity receptor for LPS. Cd14-deficient mice were found to be extremely resistant to the effect of LPS, with 100% survival and almost no detectable clinical signs following challenge with 10 times the LD 100 for control mice.…”

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

“…6a). Like others, we were unable to detect TNF in the serum of Salmonella-infected CBA/Ca mice (35,36), although this cytokine is clearly involved in innate resistance to S. typhimurium in this model (35,36). Since CsA is a widely used immunosuppressive drug that also suppresses T lymphocyte-dependent immune responses (37), which are implicated in graft rejection (11-13), we further tested the infection model under CsA immunosuppression.…”