Viral Infections

A number of specific immune effector mechanisms, together with nonspecific defense mechanisms, are called into play to eliminate an infecting virus (Table 17-1). At the same time, the virus acts to subvert one or more of these mechanisms to prolong its own survival. The outcome of the infection depends on how effectively the host's defensive mechanisms resist the offensive tactics of the virus.

The innate immune response to viral infection is primarily through the induction of type I interferons (IFN-a and IFN-p) and the activation of NK cells. Double stranded RNA (dsRNA) produced during the viral life cycle can induce the expression of IFN-a and IFN-p by the infected cell. Macrophages, monocytes, and fibroblasts also are capable of synthesizing these cytokines, but the mechanisms that induce the production of type I interferons in these cells are not completely understood. IFN-a and IFN-p can induce an antiviral response or resistance to viral replication by binding to the IFN a/p receptor. Once bound, IFN-a and IFN-p activate the JAK-STAT pathway, which in turn induces the transcription of several genes. One of these genes encodes an

Mechanisms of humoral and cell-mediated immune responses to viruses

Response type

Effector molecule or cell

Activity

Humoral

Antibody (especially, secretory IgA) IgG, IgM, and IgA antibody IgG and IgM antibody IgM antibody

Complement activated by IgG or IgM antibody

Blocks binding of virus to host cells, thus preventing infection or reinfection Blocks fusion of viral envelope with host-cells plasma membrane Enhances phagocytosis of viral particles

(opsonization) Agglutinates viral particles Mediates opsonization by C3b and lysis of enveloped viral particles by membrane-attack complex

Cell-mediated

IFN-7 secreted by TH or TC cells Cytotoxic T lymphocytes (CTLs) NK cells and macrophages

Has direct antiviral activity Kill virus-infected self-cells Kill virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC)

Rhinovirus Attacking Cells

Protein kinase PKR (inactive)

+ ATP and dsRNA

Inactive RNAse L

Active RNAse L

Protein kinase PKR (inactive)

PKR (activated)

Phosphorylation of eIF-2

+ ATP and dsRNA

Degradation of eIF2-GDP poly(A)mRNA (nonfunctional)

Degradation of eIF2-GDP poly(A)mRNA (nonfunctional)

INHIBITION OF PROTEIN SYNTHESIS

INHIBITION OF PROTEIN SYNTHESIS

face receptor molecules that enable them to initiate infection by binding to specific host-cell membrane molecules. For example, influenza virus binds to sialic acid residues in cellmembrane glycoproteins and glycolipids; rhinovirus binds to intercellular adhesion molecules (ICAMs); and Epstein-Barr virus binds to type 2 complement receptors on B cells. If antibody to the viral receptor is produced, it can block infection altogether by preventing the binding of viral particles to host cells. Secretory IgA in mucous secretions plays an important role in host defense against viruses by blocking viral attachment to mucosal epithelial cells. The advantage of the attenuated oral polio vaccine, considered in Chapter 18, is that it induces production of secretory IgA, which effectively blocks attachment of poliovirus along the gastrointestinal tract.

Viral neutralization by antibody sometimes involves mechanisms that operate after viral attachment to host cells. In some cases, antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of the viral envelope with the plasma membrane. If the induced antibody is of a complement-activating isotype, lysis of enveloped virions can ensue. Antibody or complement can also agglutinate viral particles and function as an opsonizing agent to facilitate Fc- or C3b-receptor-mediated phagocytosis of the viral particles.

FIGURE 17-2

Induction of antiviral activity by IFN-a and -p. These interferons bind to the IFN receptor, which in turn induces the synthesis of both 2-5(A) synthetase and protein kinase (PKR). The action of of 2-5(A) synthetase results in the activation of RNAse L, which can degrade mRNA. PKR inactivates the translation initiation factor eIF-2 by phosphorylating it. Both pathways thus result in the inhibition of protein synthesis and thereby effectively block viral replication.

enzyme known as 2'-5'-oligo-adenylate synthetase [2-5(A) synthetase], which activates a ribonuclease (RNAse L) that degrades viral RNA. Other genes activated by IFN-a/p binding to its receptor also contribute to the inhibition of viral replication. For example, IFN-a/p binding induces a specific protein kinase called dsRNA-dependent protein kinase (PKR), which inactivates protein synthesis, thus blocking viral replication in infected cells (Figure 17-2).

The binding of IFN-a and IFN-p to NK cells induces lytic activity, making them very effective in killing virally infected cells. The activity of NK cells is also greatly enhanced by IL-12, a cytokine that is produced very early in a response to viral infection.

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