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


    ; 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.



    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.


    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.


    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


    ; 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


    ; 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.


    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.


    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


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.

    Whereas most inhibitors block only one or a few viruses, some have

    a broad antiviral spectrum. Although the effectiveness of the

    inhibitors has not been fully established in vivo, their importance as

    host defenses is suggested by their antiviral activity in tissue culture

    and in vivo and by the direct correlation between the degree of

    virulence of some viruses and their degree of resistance to certain

    inhibitors. Examples are the serum and mucus inhibitors of influenza

    viruses during experimental infections. However, even sensitive

    viruses may overwhelm these inhibitors when the infecting dose of

    virus is sufficiently high. Therefore, the presence of these inhibitors

    may explain the relatively high dose of virus required to initiate

    infection in vivo, compared with the dose needed in cell cultures. Phagocytosis

    The limited information available suggests that phagocytosis is less

    effective against viral infections than against bacterial infections.

    However, few of the factors that control uptake of virions or infected cells by phagocytes and their digestion by lysosomal enzymes have been studied systemically. Different viruses are affected differently by the various phagocytic cells. Some viruses are not engulfed, whereas


others are engulfed but may not be inactivated. In fact, some viruses,

    such as human immunodeficiency virus (HIV), may even multiply in the phagocytes (e.g., macrophages), which may serve as a persistent

    reservoir of virus (Fig. 49-1). The virulence of several strains of HIV and herpesviruses correlates with their ability to multiply in macrophages.

    Infected macrophages may carry virus across the blood-brain barrier.

    Interestingly, cytomegalovirus has been reported to replicate in granulocytes.

     Macrophages seem to be more effective against viruses than are

    granulocytes, and some viruses seem to be more susceptible to phagocytosis than others. Macrophages and polymorphonuclear leukocytes can afford important protection by markedly reducing the viremia caused by virus strains susceptible to phagocytosis.

FIGURE 49-1 Possible outcomes of phagocytosis of a virus.

    Viruses may stimulate macrophages to produce monokines, which can

    reduce viral multiplication. For example,

    macrophage-produced alpha interferon (IFN-a) inhibits viral

    multiplication both directly and also indirectly by activating natural

    killer cells.


Interleukin 1 (IL-1), produced by macrophages, can interfere with viral

    multiplication in a number of ways:

    ; by inducing T lymphocytes to produce interleukin-2, which in turn

    induces gamma interferon (IFN-g), which can induce alpha and

    beta interferons;

    ; by inducing the production of beta interferon (IFN-b) by

    fibroblasts and epithelial cells;

    ; by inducing fever, which inhibits viral replication;

    ; by enhancing macrophage-mediated cytolysis of infected cells;


    ; by inducing production of tumor necrosis factor (TNF), which

    inhibits virus multiplication both directly and indirectly by

    inducing interferon and other cytokines and augmenting

    inflammation, phagocytosis and cytotoxic activity. Therefore, depending on the situation, macrophages acting as


    ; may reduce the number of viruses,

    ; help spread the infection,

    ; augment or depress immune defenses, or

    ; have little effect.

    Defense Mechanisms Evoked by Infection


    Viral replication is influenced strongly by temperature. Fever can be

    induced during viral infection by at least three independent endogenous pyrogens:

    ; interleukins-1 and 6,

    ; interferon,

    ; prostaglandin E2, and

    ; tumor necrosis factor.

    Even a modest increase can cause strong inhibition: a temperature

    rise from 37?C to 38?C drastically decreases the yield of many viruses.

    This phenomenon has been observed in tissue culture as well as in

    many experimental (including primate) and natural infections.

    Artificial induction of fever reduces mortality in mice infected with

    viruses (Fig. 49-2). Artificial lowering of the temperature during

    infection may increase mortality, as in suckling mice infected with

    coxsackieviruses and taken away from the warmth of their mother's


    nest. Fever also augments the generation of cytotoxic T


    FIGURE 49-2 Protection of mice by elevated temperature or antibody

    administered before or after intracerebral infection with the

    picornavirus EMC type.

    Several observations suggest strongly that fever reduces virus

    multiplication during human viral infections.

    Retrospective studies have shown that the incidence and severity of

    paralysis among children infected with polioviruses were significantly greater in patients treated with antipyretic drugs (e.g., aspirin) than in

    untreated children.

    Also consistent with these findings is the observation that virus strains

    that replicate best at fever temperature are usually virulent, whereas

    virus strains that replicate poorly at fever temperature are usually low in virulence and therefore often are used as live virus vaccines. Temperatures as low as 33?C are normal at body surfaces exposed to

    air; viruses that infect these sites and replicate optimally at these temperatures establish only local infections that do not spread to

    deeper tissues, where the body temperature is higher. For example,

    rhinoviruses that cause common colds replicate optimally at 33?C to 34?C (found in normally ventilated nasal passages); however, they are


    inhibited at 37?C (found when swelling of the edematous mucosa and secretions interrupt air flow). An interesting question is whether this temperature increase is important for recovery from coryza. The same general considerations of temperature probably apply to other human viral infections such as measles, rubella, and mumps, although, unfortunately, suitable and controlled studies have not been conducted. Nevertheless, available information suggests that antipyretic drugs be used conservatively.


    Several antiviral mechanisms are generated by the local inflammatory response to virus-induced cell damage or to virus-stimulated mediators such as activated complement. The major components of the

    inflammatory process are

    ; circulatory alterations,

    ; edema,

    ; leukocyte accumulation and

    ; perhaps prostaglandins A and J.

    The resulting phenomena are

    ; elevated local temperature,

    ; reduced oxygen tension in the involved tissues,

    ; altered cell metabolism, and

    ; increased levels of CO2 and organic acids.

    All of these alterations, which occur in a cascading and interrelated fashion, drastically reduce the replication of many viruses. For instance,

    the altered energy metabolism of the infected and surrounding cells, as well as the accumulating lymphocytes, can generate local

    hyperthermia. At superficial sites where the temperature is normally lower, hyperthermia can also be generated by hyperemia during the early stages of inflammation. As inflammation progresses, hyperemia becomes passive, thereby greatly reducing blood flow and decreasing oxygen tension. Two factors account for this decrease in oxygen

    tension: limited influx of erythrocytes, and lower diffusion of oxygen through edema fluid. In turn, the decreased oxygen tension causes less

    ATP production, thus reducing the energy available for viral synthesis

    and increasing anaerobic glycolysis, which increases the accumulation

    of CO2 and organic acids in the tissues. These acid catabolites may

    decrease the local pH to levels that inhibit the replication of many viruses. Local acidity also may increase by accumulation and subsequent degradation of the leukocytes in the affected area. It is

    possible that other less well-defined factors are also significant .


    Therefore, the local inflammation resulting from viral infection clearly activates several metabolic, physicochemical, and physiologic changes; acting individually or together, these changes interfere with virus multiplication. Although further animal and human studies are required, this interpretation is supported by the finding that anti-

    inflammatory drugs (corticosteroids) often increase the severity of infection in animals. Therefore, these drugs should be used with caution in treating viral diseases.

    Viral Interference and Interferon

    Viral Interference

    Generally, infection by one virus renders host cells resistant to other, superinfecting viruses. This phenomenon, called viral interference, occurs frequently in cell cultures and in animals (including humans).

    Although interference occurs between most viruses, it may be limited to homologous viruses under certain conditions.

    1. Some types of interference are caused by competition among

    different viruses for critical replicative pathways

    ; extracellular competition for cell surface receptors,

    ; intracellular competition for biosynthetic machinery and genetic


    2. Similar interference may result from competition between

    defective (nonmultiplying) and infective viruses that may be

    produced concurrently.

    3. Another type of interference the most important type in natural

    infectionsis directed by the host cells themselves.

    These infected cells may respond to viral infection by producing

    interferon proteins, which can react with uninfected cells to render

    them resistant to infection by a wide variety of viruses. Interferon

    The important role played by interferon as a defense mechanism is

    clearly documented by three types of experimental and clinical


    (1) for many viral infections, a strong correlation has been

    established between interferon production and natural



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