A Neutrophil-Derived Anti-Infective Molecule: Bactericidal/Permeability-Increasing Protein

Effective host defense against microbial invasion requires an innate immune system whose response is both rapid and independent of prior exposure (25). The neutrophil is a central cellular effector of the innate immune system whose importance to host defense is manifest in the increased frequency and severity of infections in patients who have defects in neutrophil quantity or quality. The mechanisms by which neutrophils exert their antimicrobial activity have been under investigation since the seminal work of Eli Metchnikoff, who demonstrated the phagocytic activity of these cells at the beginning of the 20th century. Activated neutrophils increase oxygen consumption during inflammatory responses in what has been termed the “respiratory burst,” reflecting assembly of a multicomponent neutrophil oxidase which transfers electrons to molecular oxygen, forming toxic radicals (6). Defects in the phagocyte oxidase proteins underlie chronic granulomatous disease (CGD), which is characterized by increased frequency of infections with certain bacterial and fungal pathogens (38). Nitric oxide is another small, readily diffusible antimicrobial mediator generated by activated neutrophils (54). Over the past two decades, there has been increasing recognition of oxygen-independent killing mechanisms relating to the following observations: (i) neutrophils from CGD patients are capable of killing a variety of microorganisms (52), (ii) normal neutrophils deprived of oxygen in vitro are also able to efficiently kill certain bacterial pathogens (52), (iii) crude acid extracts of neutrophils possess direct microbicidal activity which is oxygen independent (24), and (iv) cationic proteins and peptides isolated from such extracts are able to directly kill microorganisms in vitro (29). Encouraged by these observations, investigators have made use of protein chromatography and molecular cloning in order to isolate, sequence, and define a growing number of neutrophil granule-derived antimicrobial proteins and peptides (15, 22, 23). Neutrophil protein and peptide antibiotics are deployed by degranulation either extracellularly into inflammatory fluids or intracellularly into the phagolysosome, thereby exposing microorganisms to high concentrations of these agents. The antimicrobial proteins and peptides share in common a net positive charge which contributes to electrostatic interactions with negatively charged microbial surface components. However, despite similar charges, these agents vary markedly in size and structure as well as the mechanisms and selectivities of their cytotoxic actions. Here the focus is on a remarkably selective anti-infective component of human neutrophils known as the bactericidal/permeability-increasing protein (BPI).