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.

How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria

“…[15] Moreover, patients who are treated with complement inhibitors such as the C5 inhibitor eculizumab are more prone to infections with Gram-negative bacteria. [13] Taken together, since these early observations of Bordet, it has become evident that MAC pores play a central role in clearing Gram-negative bacteria.…”

“…[1,2] Complement activation occurs at the cell surface and triggers a proteolytic cascade, which activates soluble complement proteins that circulate as inactive precursors in the blood. Clinically, this is relevant in the pathogenesis of infectious diseases and malignancies as well as in autoimmunity and inflammatory disorders (reviewed in Heesterbeek et al [13] ). [3] Since these bactericidal effects were only observed in the serum of vaccinated individuals, Bordet annotated this as a system that "complements" the clearance of bacteria.…”

“…It was decades later, from the late 1960s until the early 1980s, that the killing in serum was attributed to cytolysis by pores. [13] Taken together, since these early observations of Bordet, it has become evident that MAC pores play a central role in clearing Gram-negative bacteria. [7][8][9][10][11] Complement activation and MAC assembly can occur on many different cell surfaces, such as those of bacteria, parasites, enveloped viruses, and aberrant host cells (reviewed in Dunkelberger and Song [12] ).…”

“…[7][8][9][10][11] Complement activation and MAC assembly can occur on many different cell surfaces, such as those of bacteria, parasites, enveloped viruses, and aberrant host cells (reviewed in Dunkelberger and Song [12] ). Clinically, this is relevant in the pathogenesis of infectious diseases and malignancies as well as in autoimmunity and inflammatory disorders (reviewed in Heesterbeek et al [13] ). In this review, we will focus on MAC pores in the context of bacteria.…”

Catch Me if You Can or Actors on the Run

“…The review article by Emert and Laabei [1], published in this issue, provides the reader with an excellent and a timely overview of the tricks employed by these bacteria to fool the immune system. Recent studies have underlined the importance of complement in eradicating invading bacteria [2] or being involved in other essential innate immune pathways such as the kallikrein/kinin system [3], making the complement system an interesting target for drug development [4]. However, as exemplified by Laabei and Ermert, bacteria are often one step ahead, which makes hunting the catch a difficult undertaking.…”