Immune subversion is also practiced by protozoan parasites. Leishmania major, which is transmitted to dermal tissues of humans by the bite of sandflies, is an obligate intracellular parasite that replicates within tissue macrophages. As is true of other intracellular pathogens that reside within phagocytic vesicles, eradication of L. major is dependent on a type 1 immune response. Through mechanisms that are incompletely understood, L. major specifically inhibits the production of IL12 by its macrophage host, thereby inhibiting the production of IFNγ by NK cells and inhibiting the differentiation and function of TH1 cells. In addition, L. major has been shown to actively induce IL10producing Treg cells that suppress clearance of the infection.
13-22 RNA viruses use different mechanisms of antigenic variation to keep a step ahead of the adaptive immune system.
Viruses are both the simplest and most diverse of pathogens. They can replicate only within living cells, relying on host cellular machinery to replicate and propagate themselves. As obligate intracellular pathogens, they activate intracellular PRRs that sense viral genetic material and provoke cytolytic immune responses by innate and adaptive immune cells—NK cells and CD8 T cells, respectively. They also induce type I interferon responses, which activate cellintrinsic mechanisms to limit viral replication in both infected and uninfected cells. Although many cells produce type I interferons, plasmacytoid dendritic cells are innate sensor cells that are specialized for high levels of type I interferon production early in viral infections and, along with NK cells, play a central role in early antiviral host defense before the adaptive response matures. The latter involves all arms of adaptive immunity: induction of TH1 cells that provide help for production of opsonizing and complementfixing virusspecific antibodies that block viral entry into uninfected cells and activate complement to destroy enveloped viruses; and cytolytic CD8 T cells, which destroy virally infected cells and produce IFNγ.
The strategies used by viruses to defeat immune defenses are as varied as the pathogens themselves. However, some general strategies relate to the type of viral genome. RNA viruses must replicate their genomes using RNA polymerases, which lack the proofreading ability of DNA polymerase. A consequence of this is that RNA viruses have a greater rate of mutation than DNA viruses, with the practical consequence that RNA viruses cannot support large genomes. However, this also affords them opportunities for rapidly altering antigenic epitopes targeted by the adaptive immune system as a mechanism for immune evasion. Further, some RNA viruses have segmented genomes, which lend themselves to reassortment during viral replication. Both of these mechanisms are used by influenza virus, a common seasonal viral pathogen that causes acute infections and has been responsible for several major pandemics. At any one time, a single virus type is responsible for most cases of influenza throughout the world. The human population gradually develops protective immunity to this virus type, chiefly through the production of neutralizing antibody directed against the viral hemagglutinin, the main surface protein of the influenza virus. Because the virus is rapidly cleared from immune individuals, it might be in danger of running out of potential hosts were it not able to use both mutation mechanisms to alter its antigenic type (Fig. 13.22).