IMMUNOLOGY - Roit A. - Mir 2000

Chapter 16. Antiviral Immunity

INNATE ANTIVIRAL IMMUNITY

The early stage of infection typically involves a tug-of-war between the invading virus and the host's defense systems. The primary defense barrier consists of the Skin and mucosal membranes, which physically prevent viral entry. If this barrier is breached, rapid non-specific defense mechanisms (i.e., innate Immunity) are immediately engaged, involving interferons, NK Cells (natural killers), and macrophages.

Interferons inhibit viral Replication

Three types of interferons (IFNs) are known:

✵ IFNα — leukocyte interferon, encoded by a family of approximately 20 genes located on chromosome 9;

✵ IFNβ — fibroblast interferon, encoded by a single Gene located on chromosome 9, and

✵ IFNγ — immune interferon, encoded by a single gene located on chromosome 12.

Viral infection of a Cell triggers the synthesis of IFNα/β. Interferons stimulate defense mechanisms in neighboring cells, conferring resistance to viral infection (Fig. 16.4). This activation affects The genes of several Proteins, including two with direct antiviral activity. One is protein kinase (molecular mass 67 kDa), which phosphorylates the α-subunit of the Translation initiation factor eIF-2, thereby inactivating it and blocking viral Protein Synthesis. The other enzyme is 2',5'-oligoadenylate synthetase, which activates a normally latent endonuclease capable of degrading viral RNAs.

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Fig. 16.4. Following exposure to interferons (over the course of several hours), The Cell acquires resistance to the virus lasting 1-2 days.

There are also other, more specific mechanisms underlying the antiviral action of interferons. For instance, the Mx protein (a product of the Mx gene activated by α- and/or β-interferons) suppresses primary METABOLISM/31.html">Transcription of Influenza virus genes, yet has little to no effect on other Viruses. Like other interferon types, IFNγ inhibits viral replication in cells, but it additionally enhances the specific Immune Response by stimulating increased expression of MHC class I and II molecules, as well as robustly activating macrophages and NK cells (see below). The crucial role of interferons in maintaining overall antiviral resistance is evidenced by the heightened susceptibility to viral infections observed in mice following the administration of anti-interferon Antibodies.

Natural killer cells lyse virus-infected host cells

Active NK cells (natural killer cells) emerge as early as two days post-infection of the host. They serve as the primary effector mechanism in resisting herpesvirus infections, particularly cytomegalovirus (CMV) infection. A deficiency or reduction in their activity, such as in patients with Chédiak-Higashi syndrome or mice with the beige mutation, leads to increased susceptibility to cytomegalovirus. It remains unclear precisely which molecules On the surface of virus-infected host cells are recognized by NK cells. However, it is established that the extent of target cell lysis is inversely proportional to their level of MHC class I molecule expression. (This is a notable finding, given that several viruses have now been shown to downregulate host cell MHC class I expression, presumably to evade T-Cell Recognition.) Interferon-gamma enhances the functional activity of NK cells, enabling them to accumulate at sites of infection in a pre-activated state. Primarily, NK cells mediate antibody-dependent cellular cytotoxicity (ADCC).