Figure 24–7 The principal stages in complement activation by the classical, lectin, and alternative pathways. In all three pathways, the reactions of complement activation usually take place on the surface of an invading microbe, such as a bacterium, and lead to the cleavage of c3 and the various consequences shown. As indicated, the complement proteins c1 to c9, mannose-binding lectin (MBL), MBL-associated serine protease (MASp), and factors B and D are the central components of the complement system. The early components are shown within gray arrows, while the late components are shown within a brown arrow. The functions of the protein fragments produced during complement activation are indicated by the black arrows. The various complement proteins that regulate the system are omitted.
ability of these cells to make antibodies against various microbial molecules on C3b-coated pathogens; the smaller fragment of C3 (called C3a), as well as small fragments of C4 and C5, act independently as diffusible signals to promote an inflammatory response by recruiting leukocytes to the site of infection.
As indicated in Figure 24–7, antibodies bound to the surface of a pathogen activate the classical pathway. Mannose‑binding lectin, mentioned earlier, is a secreted PRR that initiates the lectin pathway of complement activation when it recognizes bacterial or fungal glycolipids and glycoproteins bearing terminal mannose and fucose sugars in a particular spatial conformation. These initial binding events in the classical and lectin pathways cause the recruitment and activation of the early complement components. Finally, molecules on the surface of pathogens will often directly activate the alternative pathway.
Host cells produce various plasma membrane molecules that prevent complement reactions from proceeding on their cell surface. The most important of these is the carbohydrate moiety sialic acid, a common constituent of cell-surface glycoproteins and glycolipids (see Figure 10–16). Because pathogens generally lack sialic acid, they are singled out for complement-mediated destruction, while host cells are spared. Some pathogens, including the bacterium Neisseria gonorrhoeae that causes the sexually transmitted disease gonorrhea, coat themselves with a layer of sialic acid to effectively hide from the complement system.
Membrane-immobilized C3b, produced by any of the three pathways, triggers a further cascade of reactions that leads to the assembly of the late complement components to form membrane attack complexes. These protein complexes assemble in the pathogen membrane near the site of C3 activation, forming aqueous pores through the membrane (Figure 24–8). For this reason, and because they perturb the structure of the lipid bilayer in their vicinity, they make the membrane leaky and can, in some cases, cause the microbe to lyse.
The self-amplifying, inflammatory, and destructive properties of the complement cascade make it essential that key activated components be rapidly inactivated after they are generated, ensuring that the attack does not spread to nearby host cells. Inactivation is achieved in at least two ways. First, specific inhibitor proteins in the blood or on the surface of host cells terminate the cascade, by either binding or cleaving certain complement components once the components have been activated by proteolytic cleavage. Second, many of the activated components in the cascade are unstable; unless they bind immediately to either the next component in the complement cascade or to a nearby membrane, they rapidly inactivate.
Virus-Infected cells Take Drastic Measures to prevent Viral replication
Because host-cell ribosomes make a virus’s proteins and host-cell lipids form the membranes of enveloped viruses, PAMPs are generally not present on the surface of viruses. Therefore, the only general way that a host cell PRR can recognize the presence of a virus is to detect unusual elements of the viral genome, such as the