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Baron S, editor. Medical Microbiology. fourth edition. Galveston (TX): College of Texas Medical Branch at Galveston; 1996.


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General Concepts

Many viral infections are restricted by defenses that are antigen nonspecific and/or certain. Noncertain defenses act sooner than particular defenses. Some are constantly in area (anatomic obstacles, noncertain inhibitors, and also phagocytic cells); others are evoked by the infection (fever, inflammation, and interferon).


Anatomic Barriers

Anatomic barriers are situated at body surencounters (skin and mucosa) or within the body (endothelial cells and also basement membranes). They are partially efficient in avoiding virus spreview but might be breached by huge numbers of virus, by trauma, by raised permecapability, by replication of virus in endothelial cells, or by transport of virus in leukocytes.


Nonspecific Inhibitors

Body fluids and also tproblems usually contain soluble viral inhibitors. Many proccasion viral attachment, some straight inactivate virsupplies, and also others act intracellularly. These inhibitors might be overwhelmed by adequate virus.


Phagocytosis

Viruses may be phagocytosed to various levels by polymorphonuclear leukocytes and macropheras. The effect of phagocytosis might be virus inactivation, persistence, or multiplication; subsequently, the result might be clearance of virus, transport to remote sites, or enhanced infection.


Fever

Replication of a lot of virprovides is decreased by even a modest increase in temperature. During viral infection, fever can be initiated by numerous endogenous pyrogens, such as interleukins-1 and -6, interferon, prostaglandin E2, and tumor necrosis element.


Inflammation

Inflammation inhibits viral replication via (1) elevated neighborhood temperature, (2) diminished oxygen stress and anxiety, (3) metabolic alterations, and also (4) acid manufacturing. The effects of these mechanisms are regularly additive.


Viral Interference and Interferon

Viral interference occurs once infection by one virus renders cells resistant to the same or other superinfecting viroffers. Interference is commonly mediated by recently induced hold cell proteins designated as the interferon devices. Secreted interferon binds to cells and induces them to block various steras of viral replication. Interferon also (1) inhibits growth of some normal and also tumor cells and also of many type of intracellular parasites, such as rickettsiae and protozoa; (2) modulates the immune response; and (3) affects cell differentiation. Tright here are 3 main kinds of interferon, alpha, beta, and gamma interferons. Alpha interferon is produced largely by specific leukocytes (dendritic cells, macrophperiods and also B cells), beta interferon by epithelial cells and fibroblasts, and gamma interferon by T and also organic killer cells. Two other interferon forms are concerned alpha interferon. Omega interferons share about seventy percent identity with alpha interferons. Tau interferons additionally are related structurally to alpha interferons yet are unusual by (a) being created for just a few days by normal placental trophoblasts and (b) not being inducible by virsupplies.


Introduction

Most viral infections are limited by nonparticular defenses, which (1) restrict initial virus multiplication to controlled levels, (2) initiate recoextremely from established infections that is then completed by a mix of these early on nonparticular and also succeeding antigen-certain immune defenses, and also (3) enable the organize to cope via the top numbers of virus that, if presented as the infecting dose, can be lethal. Although immune and also nonimmune (nonspecific) defenses run together to manage viral infections, this chapter considers only nonparticular defenses. Some nonspecific defenses exist separately of infection (e.g., genetic factors, anatomic barriers, nonparticular inhibitors in body fluids, and phagocytosis). Others (e.g., fever, inflammation, and interferon) are developed by the hold in response to infection. All nonspecific defenses start to act before the particular defense responses build and also deserve to potentiate some of the establiburned immune effector mechanisms.

The reality that virsupplies replicate intracellularly and the ability of some virsupplies to spcheck out by inducing cell fusion partially safeguard virsupplies against such extracellular defenses as neutralizing antibody, phagocytosis, and also nonparticular inhibitors. However before, bereason they replicate within the cell, virprovides are breakable to intracellular alterations caused by organize responses to infection. Nonparticular responses that transform the intracellular atmosphere include fever, inflammation, and interferon.

These multiple defenses feature through excellent intricacy because of their interactions via one another. This complexity is compounded by the differing effectiveness of the defenses that results from the diversity of virprovides, hosts, and sites and stages of infection.


Anatomic Barriers

Anatomic obstacles to viroffers exist at the body surfaces and also within the body. At the body surencounters, the dead cells of the epidermis and also any kind of live cells that might lack viral receptors stand up to virus penetration and also execute not permit virus replication. However before, this obstacle is conveniently bgot to, for instance, by pet bites (rabies virus), insect bites (togaviruses), and also minor traumas (wart virus). At mucosal surencounters, just the mucus layer stands between invading virus and also live cells. The mucus layer develops a physical obstacle that entraps international pposts and also carries them out of the body; it also includes nonspecific inhibitors (see following section). The mucus barrier is not absolute, yet, because enough quantities of many kind of viroffers can overwhelm it and infect by this route. In truth, most viroffers usage mucous surdeals with as the portal of entry and also initial replication website.

Within the body, anatomic obstacles to virus spread are created by the layer of endothelial cells that separates blood from tproblems (e.g., the bloodbrain barrier). Under normal problems, these obstacles have actually a low permecapacity for viroffers unless the virus can penetrate them by replicating in the capillary endothelial cells or in circulating leukocytes. These internal obstacles may define, in component, the high level of viremia forced to infect organs such as the brain, placenta, and also lungs.


Nonspecific Inhibitors

A number of viral inhibitors take place naturally in most body fluids and also tissues. They differ chemically (lipids, polysaccharides, proteins, lipoproteins, and also glycoproteins) and also in the level of viral inhibition and also types of virsupplies affected. Some inhibitors are related to the viral receptors of the cell surface, yet the majority of are of unwell-known origin. Many kind of inhibitors act by avoiding virus from attaching to cells, others by straight inactivating virus, and also a few by inhibiting virus replication. In the gastrointestinal tract, some vulnerable viruses are inset off by acid, bile salts, and enzymes. Whereas the majority of inhibitors block only one or a couple of viruses, some have actually a large antiviral spectrum. Although the effectiveness of the inhibitors has actually not been fully established in vivo, their prominence as host defenses is argued by their antiviral task in tconcern culture and also in vivo and by the straight correlation in between the degree of virulence of some viroffers and also their level of resistance to certain inhibitors. Instances are the serum and also mucus inhibitors of influenza virsupplies in the time of experimental infections. However, also sensitive virsupplies might overwhelm these inhibitors as soon as the infecting dose of virus is sufficiently high. Because of this, the visibility of these inhibitors may explain the relatively high dose of virus forced to initiate infection in vivo, compared via the dose necessary in cell societies.


Phagocytosis

The limited information easily accessible argues that phagocytosis is less reliable versus viral infections than versus bacterial infections. However, few of the determinants that manage uptake of virions or infected cells by phagocytes and also their digestion by lysosomal enzymes have been studied systemically. Different viroffers are influenced in different ways by the various phagocytic cells. Some viruses are not engulfed, whereas others are engulfed yet might not be incaused. In reality, some virprovides, such as humale immunodeficiency virus (HIV), might 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 herpesvirsupplies correlates via their ability to multiply in macropheras. Infected macrophperiods might bring virus throughout the blood-brain obstacle. Interestingly, cytomegalovirus has been reported to replicate in granulocytes. Macrophages seem to be even more effective against virprovides than are granulocytes, and also some virsupplies seem to be even more vulnerable to phagocytosis than others. Macrophages and also polymorphonuclear leukocytes can afford crucial security by markedly reducing the viremia resulted in by virus strains susceptible to phagocytosis.


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Virsupplies may stimulate macrophperiods to develop monokines, which can mitigate viral multiplication. For instance, macrophage-produced alpha interferon (IFN-α) inhibits viral multiplication both directly and additionally instraight by activating natural killer cells. Interleukin 1 (IL-1), produced by macropheras, deserve to interfere with viral multiplication in a number of ways: (1) by inducing T lymphocytes to develop interleukin-2, which consequently induces gamma interferon (IFN-γ), which have the right to induce alpha and also beta interferons; (2) by inducing the manufacturing of beta interferon (IFN-β) by fibroblasts and epithelial cells; (3) by inducing fever before, which inhibits viral replication; (4) by boosting macrophage-mediated cytolysis of infected cells; and also (5) by inducing production of tumor necrosis aspect (TNF), which inhibits virus multiplication both directly and indirectly by inducing interferon and also other cytokines and also augmenting inflammation, phagocytosis and cytotoxic task. As such, depending on the situation, macropheras acting as phagocytes may alleviate the number of viroffers, help spcheck out the infection, augment or depush immune defenses, or have actually little effect.


Fever

Viral replication is affected strongly by temperature. Fever before have the right to be induced during viral infection by at leastern 3 independent endogenous pyrogens: interleukins-1 and 6, interferon, prostaglandin E2, and tumor necrosis aspect. Even a modest increase have the right to reason solid inhibition: a temperature climb from 37°C to 38°C drastically decreases the yield of many kind of viruses. This phenomenon has been oboffered in tconcern culture and also in many kind of experimental (including primate) and organic infections. Artificial induction of fever before reduces mortality in mice infected via virprovides (Fig. 49-2). Artificial lowering of the temperature throughout infection may increase mortality, as in suckling mice infected with coxsackievirprovides and also taken ameans from the warmth of their mother"s colony. Fever also augments the generation of cytotoxic T lymphocytes.


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Figure 49-2

Protection of mice by elevated temperature or antibody administered before or after intracerebral infection via the picornavirus EMC type.


Several monitorings imply strongly that fever before reduces virus multiplication during humale viral infections. Retrospective researches have displayed that the incidence and severity of paralysis among children infected through poliovirsupplies were significantly better in patients treated through antipyretic drugs (e.g., aspirin) than in untreated youngsters. Also constant through these findings is the observation that virus strains that replicate ideal at fever temperature are generally virulent, whereas virus strains that replicate poorly at fever before temperature are normally low in virulence and therefore often are supplied as live virus vaccines.

Temperatures as low as 33°C are normal at body surdeals with exposed to air; viruses that infect these sites and replicate optimally at these temperatures establish just local infections that execute not spread to deeper tproblems, wbelow the body temperature is greater. For instance, rhinoviroffers that reason common colds replicate optimally at 33°C to 34°C (discovered in generally ventilated nasal passages); however, they are inhibited at 37°C (found as soon as swelling of the edematous mucosa and secretions interrupt air flow). An interesting question is whether this temperature rise is vital for recoextremely from coryza. The same general considerations of temperature probably use to other humale viral infections such as measles, rubella, and also mumps, although, unfortunately, suitable and controlled research studies have not been carried out. Nonetheless, easily accessible indevelopment suggests that antipyretic drugs be provided conservatively.


Inflammation

Several antiviral mechanisms are created by the regional inflammatory response to virus-induced cell damage or to virus-engendered mediators such as caused enhance. The significant components of the inflammatory procedure are circulatory alterations, edema, leukocyte accumulation and also maybe prostaglandins A and also J. The resulting phenomena are elevated regional temperature, reduced oxygen anxiety in the connected tissues, altered cell metabolism, and increased levels of CO2 and also organic acids. All of these alterations, which happen in a cascading and interconnected fashion, substantially minimize the replication of many type of virprovides. For instance, the transformed energy metabolism of the infected and surrounding cells, and the accumulating lymphocytes, can generate local hyperthermia. At superficial sites wright here the temperature is typically lower, hyperthermia can likewise be created by hyperemia during the at an early stage stperiods of inflammation. As inflammation progresses, hyperemia becomes passive, thereby significantly reducing blood flow and decreasing oxygen anxiety. Two components account for this decrease in oxygen tension: limited influx of erythrocytes, and reduced diffusion of oxygen through edema liquid. In revolve, the decreased oxygen stress reasons less ATP production, for this reason reducing the energy obtainable for viral synthesis and also raising anaerobic glycolysis, which increases the build-up of CO2 and also organic acids in the tworries. These acid catabolites might decrease the regional pH to levels that inhilittle the replication of many type of viruses. Local acidity likewise may boost by accumulation and succeeding destruction of the leukocytes in the affected area. It is possible that other much less well-characterized factors are also substantial .

Therefore, the regional inflammation resulting from viral infection clearly activates several metabolic, physicochemical, and physiologic changes; acting individually or together, these alters interfere via virus multiplication. Although additionally pet and huguy studies are forced, this interpretation is sustained by the finding that anti-inflammatory drugs (corticosteroids) regularly rise the severity of infection in pets. As such, these drugs have to be supplied with caution in dealing with viral conditions.


Viral Interference

Usually, infection by one virus makes host cells resistant to various other, superinfecting viroffers. This phenomenon, referred to as viral interference, occurs typically in cell societies and also in pets (including humans). Although interference occurs between the majority of virprovides, it may be restricted to homologous virsupplies under certain problems. Some types of interference are resulted in by competition among different viruses for critical replicative pathways (extracellular competition for cell surconfront receptors, intracellular competition for bioartificial machinery and hereditary control). Similar interference may outcome from competition between defective (nonmultiplying) and infective virsupplies that may be produced conpresently. Anvarious other type of interference—the most essential kind in natural infections—is directed by the hold cells themselves. These infected cells might respond to viral infection by producing interferon proteins, which deserve to react with uninfected cells to render them resistant to infection by a broad array of viroffers.


Interferon

The essential duty played by interferon as a defense system is plainly recorded by three kinds of speculative and also clinical observations: (1) for many type of viral infections, a solid correlation has been established in between interferon manufacturing and herbal recovery; (2) inhibition of interferon manufacturing or activity boosts the severity of infection; and (3) treatment with interferon protects against infection. In enhancement, the interferon system is one of the earliest showing up of well-known hold defenses, becoming operative within hours of infection.Figure 49-3 compares the at an early stage production of interferon through the level of antibody in the time of experimental infection of human beings via influenza virus. Clinical researches of interferon and also its inducers have actually shown defense versus certain viruses, consisting of hepatitis B and C viruses, papovaviroffers, rhinoviroffers, and also herpes simplex virus.


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Figure 49-3

Production of virus, interferon, and also antibody throughout speculative infection of human beings through influenza wild-kind virus. Noncertain defenses encompass anatomic barriers, inhibitors, phagocytosis, fever before, inflammation, and also IFN. Specific defenses incorporate antibody (more...)


Although interferon was initially known as an extraordinarily potent antiviral agent, it was discovered consequently to affect various other necessary cell and also body features. For example, it may improve killing by granulocytes, macrophages, herbal killer (NK) cells, and cytotoxic lymphocytes and affect the humoral immune response and the expression of cell membrane antigens and receptors. It may also lyse or inhilittle bit the department of certain cells, influence cell differentiation, and also cross-activate hormone attributes such as those of epinephrine and adrenocorticotropin (ACTH). The result of these modulations might influence many viral infections.


Interferon Production and Types

Interferon is developed de novo by cellular protein synthesis. The three forms (alpha, beta, and also gamma) differ both structurally and also antigenically and have molecular weights varying from 16,000 to 45,000. Interferons are secreted by the cell into the extracellular fluids (Fig. 49-4). Generally, virus-induced interferon is developed at about the same time as the viral progeny are released by the infected cell, therefore protecting neighboring cells from the spreading virus.


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Figure 49-4

Induction of beta interferon, alpha interferon, and also gamma interferon, respectively, by foreign nucleic acids, international cells, and also foreign antigens.


The 3 well-known forms of interferon are induced by different stimuli. Beta interferon is induced by viral and other international nucleic acids in a lot of body cells (fibroblasts, epithelial cells, and also macrophages). This induction device is portrayed inFigure 49-4 and also the peak percentage ofFigure 49-5.


Figure 49-5

Cellular events of the induction, production, and activity of interferon. Inducers of interferon react through cells to depress the interferon gene(s) (A). This leads to the manufacturing of mRNA for interferon (B). The mRNA is translated into the interferon (even more...)


Alpha interferon have the right to be induced by international cells, virus-infected cells, tumor cells, bacterial cells, and viral envelopes that stimulate greatly circulating dendritic cells and also to a lesser level monocytes and B lymphocytes to develop it (Fig. 49-4, middle).

Gamma interferon is created (along with various other lymphokines) by T lymphocytes induced by foreign antigens to which the T lymphocytes have actually been presensitized (Fig. 49-4). Mitogens for T cells might mimic this induction. Gamma interferon has actually several unusual properties: (1 ) it exerts better immunomodulatory task, consisting of activation of macropheras, than the other interferons; (2) it exerts better lytic effects than the various other interferons; (3) it potentiates the actions of various other interferons; (4) it activates cells by a device substantially various from that of the various other interferons; and also (5) it inhibits intracellular microorganisms other than virprovides (e.g., rickettsia).

The 24 genes that code for interferons alpha and also the single gene for beta in humans, are situated in adjacent positions on chromosome 9. The just gene for interferon gamma is discovered on chromosome 12. The genes for interferons alpha and beta exhilittle substantial homology yet not with interferon gamma.

Genes for interferon alpha may be differentiated into two distinct clusters on the basis of the degree of homology. As a consequence, interferon alpha comprises two households of proteins, at leastern 14 of which belengthy to the alpha-1 kind and also 2 to the alpha-2 kind (omega and tau).

Also, interferon occurs without noticeable stimulation in the plasma of patients via autoimmune diseases (such as rheumatoid arthritis, disseminated lupus erythematosus and pemphigus) and also in patients with progressed HIV infection. In these situations, an interferon antigenically similar to interferon alpha is existing however which, unchoose the latter, is partly intriggered at pH 2 (acid-labile interferon alpha). This interferon is a synergistic combination of interferons alpha (acid stable) and gamma (acid labile). Consequently, acid therapy reduces the interferon activity by inactivating the synergistic interferon gamma.


Mechanism of Action

Interferon does not inactivate viroffers directly. Instead, it prevents viral replication in neighboring cells by reacting via specific receptors on the cell membranes to derepush cellular genes that encode intracellular effector antiviral proteins, which should be synthesized prior to virus replication can be inhibited (Figs. 49-5 and49-6). Alpha and beta interferons both bind to the same form of membrane receptor; gamma interferon binds to a different receptor. The antiviral proteins more than likely inhilittle viral multiplication by inhibiting the synthesis of important viral proteins, however alternative or added inhibitory mechanisms (e.g, inhibition of transcription and also viral release) also happen. Viral protein synthesis might be inhibited by numerous biochemical alterations of cells, which may, in theory, inhilittle viral replication at the different actions displayed inFigure 49-6.


It has been displayed that the antiviral state may be transferred from interferon-treated cells to surrounding untreated cells without the continued visibility of interferon (Fig. 49-4); this transport device may even more amplify and spreview the activity of the interferon system.

The interferon system is nonparticular in 2 ways: (1) assorted viral stimuli induce the same kind of interferon, and (2) the very same kind of interferon inhibits miscellaneous virprovides. On the various other hand also, the interferon molecule is mainly certain in its activity for the animal species in which it was induced: interferon developed by pets or people mostly stimulates antiviral task only in cells of the same or very closely connected households (e.g., human interferon protects human and also monessential cells, yet not chicken cells).


Interferon During Natural Infection

The prestige of interferon in the response to particular organic virus infections varies. Much relies on the effectiveness of the virus in stimulating interferon manufacturing and on its susceptibility to the antiviral activity of interferon. Interferon protects solid tconcerns in the time of virus infection; it is additionally disseminated via the bloodstream in the time of viremia, thereby protecting far-off organs versus the spreading infection. Cells safeguarded against viral replication might remove virus by degrading the virus genome (Fig. 49-7).


Medical Applications

Interferons have been apconfirmed in several countries for therapy of viral infections (papillomas and condylomata, herpes simplex, and hepatitis B and also C) and cancers (hairy cell leukemia, chronic myelogenous leukemia, non-Hodgkin"s lymphomas, and Kaposi"s sarcoma in AIDS patients). Clinical trials likewise have actually presented performance versus cryoglobulinemia and thrombocytosis and maintenance of remission in multiple myeloma. Interferon beta has actually received governmental approval for therapy of relapsing multiple sclerosis and also interferon gamma for chronic granulomatous disease. Studies of efficiency in various other viral infections and cancers are proceeding, as are research studies via substances qualified of inducing endogenous interferon.


Conclusion

In conclusion, individual defense mechanisms assume roles of differing importance during various viral infections; in most cases, the recovery procedure is more than likely brought out by the simultaneous or sequential activity of numerous mechanisms. The visibility of multiple defenses helps define why suppression of one or a number of mechanisms does not completely abrogate host resistance to viral infections; yet, impairment of host defenses by medications offered for symptomatic relief of viral infections might bring about more severe condition. For instance, aspirin and also corticosteroids minimize the nonspecific defenses. Thus, the well-established principle of the primitive physician—“primum non nocere” (primarily do not harm)—is still valid.


Baron S: Mechanisms of recovery from viral infection. In: Smith KM; Lauffer MA (eds) Advances in Virus Research. New York: Academic Press Inc.; 10:39–64, 1963.

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Baron, S, Coppenhaver DH, Dianzani F, et al (eds). Interferon: Principles and Medical Applications. The College of Texas Medical Branch at Galveston, Galveston, Texas, 1992.