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Nonspecific Defenses

By Danielle Black,2014-05-12 07:38
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Nonspecific Defenses

Nonspecific Defenses

Ferdinando Dianzani

    Samuel Baron

General Concepts

    Most viral infections are limited by defenses that are antigen

    nonspecific and/or specific. Nonspecific defenses act sooner than

    specific defenses. Some are always in place (anatomic barriers, nonspecific inhibitors, and phagocytic cells); others are evoked by the infection (fever, inflammation, and interferon). Anatomic Barriers

    Anatomic barriers are located

    ; at body surfaces (skin and mucosa) or

    ; within the body (endothelial cells and basement membranes).

    They are partly effective in preventing virus spread but may be

    breached

    ; by large numbers of virus,

    ; by trauma,

    ; by increased permeability,

    ; by replication of virus in endothelial cells, or

    ; by transportation of virus in leukocytes. Nonspecific Inhibitors

    Body fluids and tissues normally contain soluble viral inhibitors.

    ; Most prevent viral attachment,

    ; some directly inactivate viruses, and

    ; others act intracellularly.

    These inhibitors may be overwhelmed by sufficient virus.

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Phagocytosis

    Viruses may be phagocytosed to different degrees by polymorphonuclear leukocytes and macrophages.

    The effect of phagocytosis may be

    ; virus inactivation,

    ; persistence,

    ; or multiplication;

    consequently, the result may be

    ; clearance of virus,

    ; transportation to distant sites,

    ; or enhanced infection.

    Fever

    Replication of most viruses is reduced by even a modest rise in

    temperature. During viral infection, fever can be initiated by several endogenous pyrogens, such as interleukins-1 and -6, interferon, prostaglandin E2, and tumor necrosis factor. Inflammation

    Inflammation inhibits viral replication through

    ; elevated local temperature,

    ; reduced oxygen tension,

    ; metabolic alterations, and

    ; acid production.

    The effects of these mechanisms are often additive.

    Viral Interference and Interferon

    Viral interference occurs when infection by one virus renders cells

    resistant to the same or other superinfecting viruses.

    Interference is usually mediated by newly induced host cell proteins

    designated as the interferon systems. Secreted interferon binds to cells and induces them to block various stages of viral replication.

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    Interferon also

    ; inhibits growth of some normal and tumor cells and of many

    intracellular parasites, such as rickettsiae and protozoa; ; modulates the immune response; and

     affects cell differentiation. ;

    There are three main types of interferon, alpha, beta, and gamma

    interferons.

    ; Alpha interferon is produced mainly by certain leukocytes

    (dendritic cells, macrophages and B cells),

    ; beta interferon by epithelial cells and fibroblasts, and

    ; gamma interferon by T and natural killer cells.

    ; Two other interferon types are related to alpha

    interferon.

    ; Omega interferons share about seventy percent

    identity with alpha interferons.

    ; Tau interferons also are related structurally to alpha

    interferons but are unusual by (a) being produced for only a

    few days by normal placental trophoblasts and (b) not being

    inducible by viruses.

    Introduction

    Most viral infections are limited by nonspecific defenses, which

    (1) restrict initial virus multiplication to manageable levels,

    (2) initiate recovery from established infections that is then

    completed by a combination of these early nonspecific and

    subsequent antigen-specific immune defenses, and (3) enable the host to cope with the peak numbers of virus that, if

    presented as the infecting dose, could be lethal. Although immune and nonimmune (nonspecific) defenses operate together to control viral infections, this chapter considers only nonspecific defenses. Some nonspecific defenses exist

    independently of infection (e.g., genetic factors, anatomic barriers, nonspecific inhibitors in body fluids, and phagocytosis). Others (e.g.,

    fever, inflammation, and interferon) are produced by the host in

    response to infection.

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    All nonspecific defenses begin to act before the specific defense

    responses develop and can potentiate some of the established

    immune effector mechanisms.

    The fact that viruses replicate intracellularly and the ability of some

    viruses to spread by inducing cell fusion partly protect viruses against

    such extracellular defenses as neutralizing antibody, phagocytosis, and nonspecific inhibitors.

    However, because they replicate within the cell, viruses are vulnerable

    to intracellular alterations caused by host responses to infection.

    Nonspecific responses that alter the intracellular environment include

    fever, inflammation, and interferon.

    These multiple defenses function with great complexity because of

    their interactions with one another. This complexity is compounded by the varying effectiveness of the defenses that results from the diversity of viruses, hosts, and sites and stages of infection. Defense Mechanisms that Precede Infection

    Anatomic Barriers

    Anatomic barriers to viruses exist at the body surfaces and within the body.

    At the body surfaces,

    ; the dead cells of the epidermis

    ; and any live cells that may lack viral receptors resist virus

    penetration and do not permit virus replication.

    However, this barrier is easily breached, for example, by animal bites

    (rabies virus), insect bites (togaviruses), and minor traumas (wart

    virus). At mucosal surfaces, only the mucus layer stands between

    invading virus and live cells. The mucus layer forms a physical barrier

    that entraps foreign particles and carries them out of the body; it

    also contains nonspecific inhibitors (see following section). The

    mucus barrier is not absolute, however, since sufficient quantities of

    many viruses can overwhelm it and infect by this route. In fact, most

    viruses use mucous surfaces as the portal of entry and initial

    replication site.

    Within the body, anatomic barriers to virus spread are formed by the layer of endothelial cells that separates blood from tissues (e.g., the

    bloodbrain barrier). Under normal conditions, these barriers have a low

    permeability for viruses unless the virus can penetrate them by

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replicating in the capillary endothelial cells or in circulating leukocytes.

    These internal barriers may explain, in part, the high level of viremia

    required to infect organs such as the brain, placenta, and lungs. Nonspecific Inhibitors

    A number of viral inhibitors occur naturally in most body fluids and tissues. They vary

    ; chemically (lipids, polysaccharides, proteins, lipoproteins, and

    glycoproteins) and in the

    ; degree of viral inhibition and

    ; types of viruses affected.

    ; Some inhibitors are related to the viral receptors of the cell

    surface, but

    ; most are of unknown origin.

    ; Many inhibitors act by preventing virus from attaching to cells,

    ; others by directly inactivating virus, and

    ; a few by inhibiting virus replication.

    In the gastrointestinal tract, some susceptible viruses are inactivated

    by acid, bile salts, and enzymes.