BPI23-Fcγ alleviates lethal multi-drug-resistant Acinetobacter baumannii infection by enhancing bactericidal activity and orchestrating neutrophil function

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Antibiotic resistance has become a major threat, contributing significantly to morbidity and mortality globally. Administering non-antibiotic therapy, such as antimicrobial peptides, is one potential strategy for effective treatment of multi-drug-resistant Gram-negative bacterial infections. Bactericidal/permeability-increasing protein (BPI) derived from neutrophils has bactericidal and endotoxin-neutralizing activity. However, the protective roles and mechanisms of BPI in multi-drug-resistant bacterial infections have not been fully elucidated. In this study, a chimeric BPI23-Fcγ recombined protein comprising the functional N terminus of BPI and Fcγ was constructed and expressed by adenovirus vector 5 (Ad5). Ad5-BPI23-Fcγ or recombinant BPI23-Fcγ protein significantly improved the survival of mice with pneumonia induced by a minimal lethal dose of multi-drug-resistant Acinetobacter baumannii or Klebsiella pneumoniae by ameliorating lung pathology and reducing pro-inflammatory cytokines. Transfection with Ad5-BPI23-Fcγ significantly decreased the bacterial load and endotoxaemia,which was associated with enhanced bactericidal ability and elevated the phagocytic activity of neutrophils in vitro and in vivo. In addition, Ad5-BPI23-Fcγ transfection significantly increased the recruitment of neutrophils to lung, increased the proportion and number of neutrophils in peripheral blood, and promoted the maturation of bone marrow (BM) neutrophils after drug-resistant A. baumannii infection. BPI23-Fcγ and neutrophils synergistically enhanced bactericidal activity and decreased pro-inflammatory cytokines. These results demonstrated that the chimeric BPI23-Fcγ protein protected mice from pneumonia induced by multi-drug-resistant A. baumannii infection by direct bactericidal effects and promotion of neutrophil recruitment, phagocytosis and maturation. Chimeric BPI23-Fcγ may be a promising candidate as a non-antibiotic biological agent for multi-drug-resistant A. baumannii infection.