Figure 24–8 Assembly of the late complement components to form a membrane attack complex. The cleavage of the early complement components (shown within gray arrows in Figure 24–7) results in the formation of c3bcontaining proteolytic complexes called c5 convertases (not shown). These then cleave the first of the late components, c5, to produce c5a and c5b. As illustrated, c5b rapidly assembles with c6 and c7 to form c567, which then binds firmly via c7 to the membrane. One molecule of c8 binds to the complex to form c5678. The binding of a molecule of c9 to c5678 induces a conformational change in c9 that exposes a hydrophobic region and causes c9 to insert into the lipid bilayer of the target membrane. This starts a chain reaction in which the altered c9 binds a second molecule of c9, which can then bind another molecule of c9, and so on. In this way, a ring of c9 molecules forms a large transmembrane channel in the membrane.
double-stranded RNA (dsRNA) that is an intermediate in the life cycle of many viruses and is recognized by several PRRs including the Toll-like receptor TLR3; in addition, DNA virus genomes frequently contain significant amounts of the CpG motifs discussed earlier, which can be recognized by TLR9 (see Table 24–1, p. 1300).
Mammalian cells are particularly adept at recognizing the presence of dsRNA, which activates intracellular PRRs that induce the host cell to produce and secrete two antiviral cytokines—interferon-α (IFNα) and interferon-β (IFNβ). These interferons are referred to as type I interferons to distinguish them from IFNγ, which is a type II interferon and has different functions, as we discuss later. Type I interferons act in both an autocrine fashion on the infected cells that produced it and a paracrine fashion on uninfected neighbors. They bind to a common cell-surface receptor, which activates the JAK–STAT intracellular signaling pathway (see Figure 15–56) to stimulate specific gene transcription and thereby the production of more than 300 proteins, including many cytokines, reflecting the complexity of the cell’s acute response to a viral infection.
The production of type I interferons appears to be a general response of mammalian cells to a viral infection, and viral components other than dsRNA can trigger it. The type I interferons help block viral replication in multiple ways. They activate a latent ribonuclease that nonspecifically degrades single-stranded RNA. They also indirectly activate a protein kinase that phosphorylates and inactivates the protein synthesis initiation factor eIF2 (discussed in Chapter 6), thereby shutting down most protein synthesis in the infected host cell. Apparently, by destroying most of its own RNA and transiently halting most of its protein synthesis, the host cell inhibits viral replication without killing itself. If these measures fail, the cell takes an even more extreme step to prevent the virus from replicating: it kills itself by undergoing apoptosis, often with the help of immune killer cells, as we discuss next.
Natural Killer cells Induce Virus-Infected cells to Kill Themselves