Complement and Bacterial Infections: From Molecular Mechanisms to Therapeutic Applications

Abstract

Complement is a complex protein network of plasma, and an integral part of the innate immune system. Complement activation results in the rapid clearance of bacteria by immune cells, and direct bacterial killing via large pore-forming complexes. Here we review important recent discoveries in the complement field, focusing on interactions relevant for the defense against bacteria. Understanding the molecular interplay between complement and bacteria is of great importance for future therapies for infectious and inflammatory diseases. Antibodies that support complement-dependent bacterial killing are of interest for the development of alternative therapies to treat infections with antibiotic-resistant bacteria. Furthermore, a variety of novel therapeutic complement inhibitors have been developed to prevent unwanted complement activation in autoimmune inflammatory diseases. A better understanding of how such inhibitors may increase the risk of bacterial infections is essential if such therapies are to be successful.

Keywords: Antibiotic resistance; Antibody therapy; Bacteria; Complement; Eculizumab; Infections; Inflammatory diseases; Membrane attack complex; Neisseria.

Fig. 1

Antibacterial effector functions of complement. a Complement activation results in formation of the membrane attack complex (MAC or C5b-9; blue) that rapidly kills Gram-negative bacteria (orange) without the help of immune cells. Gram-positive bacteria are resistant to MAC. b Complement labels bacteria with C3-derived products (C3b and C3bi; green) that stimulate engulfment of bacteria by phagocytes. Release of complement peptide C5a is crucial for attraction of phagocytes to the site of infection. c Bacterial labeling with C3-derived products also enhances antigen presentation to B cells and thereby triggers the development of an adaptive immune response.

Fig. 2

The complement reaction. Recognition of bacterial cells occurs via soluble pattern-recognition molecules (lectin pathway) or antibodies (classical pathway). Antibody-mediated complement activation is depicted here. C1 binds to antibodies on the surface and triggers formation of a C3 convertase enzyme that converts C3 into C3b. At high C3b densities on the surface, the C3 convertase switches substrate, from C3 to C5, and is now called a C5 convertase. C5 convertases convert C5 into the chemoattractant C5a and C5b that trigger formation of the MAC (C5b-9).