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,
; 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.
; 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 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
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
; 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
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
; 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,
; 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
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,
; 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
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
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