title: Capsular polysaccharide and O-specific antigen divergently modulate pulmonary neutrophil influx in an Escherichia coli model of gram-negative pneumonitis in rats.
abstract: Enteric gram-negative bacilli cause a severe, often life-threatening pneumonia. An improved understanding of the pathogenesis of this infection may lead to improved treatment. Nearly all of the responsible gram-negative bacilli possess capsular polysaccharides and/or an O-specific antigen as part of their lipopolysaccharide (LPS). We hypothesized that these surface polysaccharides may modulate the pulmonary host response. To investigate this, a rat pneumonitis model was used, and pulmonary neutrophil influx, a critical aspect of host defense, was measured. To assess for the effect of the capsule and O-specific antigen on this host response, three proven, isogenic derivatives that are deficient in capsular polysaccharide alone (CP9.137), the O-specific antigen moiety of the LPS alone (CP921), and both the capsular polysaccharide and O-specific antigen (CP923), as well as their wild-type parent (CP9), were used as challenge strains at various intratracheal challenge inocula (CI). Total lung myeloperoxidase (MPO), a surrogate marker for neutrophils, was measured for 15 h post-bacterial challenge. To determine the effect of capsule and the O-specific antigen on the measured MPO levels, a mathematical model was developed and used to describe the MPO levels as a function of time for each CI of each of the four strains. The results from this analysis demonstrated that in the absence of the K54 capsule, 80.7 times the CI is necessary to achieve the same maximum MPO level relative to K54 positive strains (P < 0.0001). In contrast, a diametric effect was observed in the absence of the O-specific antigen, where 0.13 times the CI was necessary to achieve the same maximum MPO level relative to O4-positive strains (P = 0.0032). No interactive effect was observed between the capsule and the O-specific antigen. These findings demonstrate that these surface polysaccharides modulate pulmonary neutrophil influx and suggest that the K54 capsular polysaccharide is a proinflammatory mediator and that the O4-specific antigen attenuates the proinflammatory response. If these speculations are substantiated, an understanding of how the capsule and the O-specific antigen modulate host response could have significant therapeutic implications. The potential use of biologic modulators directed against the host response, as well as approaches based on inactivating bacterial components (e.g., surface polysaccharides) in attempts to modify sepsis syndromes, could be developed.
authors.affiliation: Department of Medicine, State University of New York at Buffalo, Buffalo, New York 14214, USA. trusso@acsu.buffalo.edu
authors.forename: T A
authors.initials: TA
authors.lastname: Russo
authors.forename: B A
authors.initials: BA
authors.lastname: Davidson
authors.forename: R L
authors.initials: RL
authors.lastname: Priore
authors.forename: U B
authors.initials: UB
authors.lastname: Carlino
authors.forename: J D
authors.initials: JD
authors.lastname: Helinski
authors.forename: P R
authors.initials: PR
authors.lastname: Knight
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000276:immunology*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000166:cytology; D009504:Neutrophils / Q000276:immunology*; D019081:O Antigens / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D019081:O Antigens