IN VIVO ANALYSIS REVEALS A ROLE FOR HUMAN MANNOSE-BINDING PROTEIN IN ACUTE SEPSIS. • 1113

Abstract

In vitro binding studies indicate that the human mannose-binding protein(MBP) recognizes a broad range of gram-negative and gram-positive bacteria as well as yeast, certain parasites and certain virally infected cells. Crystal structures of MBP have delineated the pattern of recognition. MBP is an acute phase reactant. Our premise is that MBP is an ante-antibody that plays an immediate role in defense against infections. To test this idea, we measured MBP serum levels from 62 children with oncologic disease undergoing chemotherapy, during 84 episodes of fever and neutropenia. Importantly, patients presented within hours of onset of fever. Fifteen patients had documented sepsis; 14 bacteremia (7 gram-negative, 7 gram-positive), 1 varicella-zoster. We found that in 14 of 15 of these patients, there was an initial fall in MBP levels with trough at day 3 to 4, followed by increase in level to 2- to 3-fold baseline by day 8. MBP levels increased in 4 of 6 patients who had unexplained fever. In contrast to MBP, CRP peaked when MBP was at its nadir and then decreased as MBP increased. IL-6 was highest at presentation and rapidly returned to baseline. In vitro findings confirmed that MBP bound to the range of bacteria isolated which includedPseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Streptococcus viridans, Streptococcus pneumoniae, Staphylococcus aureus andStaphylococcus epidermidis. Our results suggest that MBP opsonizes a broad range of pathogens in vivo. The initial reduction in MBP level is consistent with MBP-pathogen interaction and clearance from the circulation. The therapeutic potential for exogenous MBP in acute sepsis may be implied from our results. (Funded by Bristol-Myers Squibb).