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

Antibiotic resistance has become a major threat, significantly contributing to morbidity and mortality globally. Administering non-antibiotic therapy, such as antimicrobial peptides, is one of potential strategy for effectively treating multidrug-resistant Gram-negative bacterial infections. Bactericidal/permeability-increasing protein (BPI) derived from neutrophils can function as bactericidal and endotoxin-neutralizing activity. However, BPI's protective roles and mechanisms in multidrug-resistant bacterial infection have not been fully elucidated. In this study, a chimerical 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 multidrug-resistant Acinetobacter baumannii or Klebsiella pneumoniae by ameliorating lung pathology and reducing proinflammatory cytokines. Transfection with Ad5-BPI23-Fcγ significantly decreased the bacterial load and endotoxemia, associated with enhanced bactericidal ability and elevated neutrophils phagocytic activity in vitro and in vivo. In addition, Ad5-BPI23-Fcγ transfection significantly increased the recruitment of neutrophils to the 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 the neutrophils synergistically enhanced the bactericidal activity and decreased proinflammatory cytokines. These results demonstrated that the chimerical BPI23-Fcγ protein protected mice from multidrug-resistant A. baumannii infection-induced pneumonia by direct bactericidal effects and promoting neutrophils recruitment, phagocytosis, and maturation. Chimerical BPI23-Fcγ may be a promising candidate of non-antibiotic biological agent for multidrug-resistant A. baumannii infection.