Fig. 2.12 Pore formation by human RegIIIα. Top: a model of the RegIIIα pore was generated by docking the human pro-RegIIIα structure (PDB ID: 1UV0), shown as individual purple and turquoise ribbon diagrams, into the cryo-electron microscopic map of the RegIIIα filament. LPS blocks the pore-forming activity of RegIIIα, explaining its selective bactericidal activity against Gram-positive but not Gram-negative bacteria. Bottom: electron microscopic images of RegIIIα pores assembled in the presence of lipid bilayers. Top structure courtesy of
L. Hooper.
The complement system and innate immunity.
a proteolytic step to complete their activation, whereupon they become capable of killing microbes by forming pores in the microbial cell membranes. The actions of antimicrobial enzymes and peptides described in this section often involve binding to unique glycan/carbohydrate structures on the microbe. Thus, these soluble molecular defenses are both pattern recognition receptors and effector molecules at the same time, representing the simplest form of innate immunity.
The complement system and innate immunity.
When a pathogen breaches the host’s epithelial barriers and initial antimicrobial defenses, it next encounters a major component of innate immunity known as the complement system, or complement. Complement is a collection of soluble proteins present in blood and other body fluids. It was discovered in the 1890s by Jules Bordet as a heat-labile substance in normal plasma whose activity could ‘complement’ the bactericidal activity of immune sera. Part of the process is opsonization, which refers to coating a pathogen with antibodies and/or complement proteins so that it can be more readily taken up and destroyed by phagocytic cells. Although complement was first discovered as an effector arm of the antibody response, we now understand that it originally evolved as part of the innate immune system and that it still provides protection early in infection, in the absence of antibodies, through more ancient pathways of complement activation.
The complement system is composed of more than 30 different plasma proteins, which are produced mainly by the liver. In the absence of infection, these proteins circulate in an inactive form. In the presence of pathogens or of antibody bound to pathogens, the complement system becomes ‘activated.’ Particular complement proteins interact with each other to form several different pathways of complement activation, all of which have the final outcome of killing the pathogen, either directly or by facilitating its phagocytosis, and inducing inflammatory responses that help to fight infection. There are three pathways of complement activation. As the antibody-triggered pathway of complement activation was discovered first, this became known as the classical pathway of complement activation. The next to be discovered was called the alternative pathway, which can be activated by the presence of the pathogen alone; and the most recently discovered is the lectin pathway, which is activated by lectin-type proteins that recognize and bind to carbohydrates on pathogen surfaces.