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Baron S, editor. Clinical Microbiology. 4th edition. Galveston (TX): university of Texas clinical Branch at Galveston; 1996.


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General Concepts

Most viral infections are restricted by defenses that are antigen nonspecific and/or specific. Nonspecific defenses action sooner than certain defenses. Part are always in ar (anatomic barriers, nonspecific inhibitors, and phagocytic cells); others space evoked by the infection (fever, inflammation, and interferon).


Anatomic Barriers

Anatomic obstacles are situated at human body surfaces (skin and mucosa) or within the human body (endothelial cells and basement membranes). They space partly efficient in avoiding virus spread however may it is in breached by big numbers that virus, by trauma, by enhanced permeability, through replication the virus in endothelial cells, or by transport of virus in leukocytes.


Nonspecific Inhibitors

Body fluids and also tissues usually contain soluble viral inhibitors. Most prevent famous attachment, some straight inactivate viruses, and also others action intracellularly. These inhibitors may be overwhelmed by adequate virus.


Phagocytosis

Viruses may be phagocytosed to different levels by polymorphonuclear leukocytes and also macrophages. The result of phagocytosis may be virus inactivation, persistence, or multiplication; consequently, the result may be clearance of virus, transportation to remote sites, or magnified infection.


Fever

Replication of many viruses is lessened by even a modest rise in temperature. During viral infection, fever can be initiated by several endogenous pyrogens, such together interleukins-1 and -6, interferon, prostaglandin E2, and tumor necrosis factor.


Inflammation

Inflammation inhibits viral replication with (1) elevated neighborhood temperature, (2) lessened oxygen tension, (3) metabolic alterations, and also (4) acid production. The results of these mechanisms are frequently additive.


Viral Interference and Interferon

Viral interference occurs once infection through one virus makes cells resistant come the same or various other superinfecting viruses. Interference is normally mediated by newly induced host cell proteins designated together the interferon systems. Secreted interferon binding to cells and also induces them to block various stages of famous replication. Interferon additionally (1) inhibits development of part normal and also tumor cells and of countless intracellular parasites, such together rickettsiae and protozoa; (2) mediate the immune response; and also (3) affects cabinet differentiation. There space three main types of interferon, alpha, beta, and gamma interferons. Alpha interferon is produced mainly by certain leukocytes (dendritic cells, macrophages and also B cells), beta interferon by epithelial cells and also fibroblasts, and gamma interferon by T and also natural killer cells. Two various other interferon species are regarded alpha interferon. Omega interferons share around seventy percent identification with alpha interferons. Tau interferons additionally are connected structurally to alpha interferons however are unusual by (a) being produced for just a couple of days by typical placental trophoblasts and also (b) no being inducible through viruses.


Introduction

Most viral infections are minimal by nonspecific defenses, i beg your pardon (1) limit initial virus multiplication to controlled levels, (2) initiate restore from developed infections the is climate completed through a mix of these early on nonspecific and also subsequent antigen-specific immune defenses, and also (3) enable the host to cope with the optimal numbers the virus that, if presented as the infecting dose, might be lethal. Return immune and also nonimmune (nonspecific) defenses operate together to control viral infections, this chapter considers just nonspecific defenses. Part nonspecific defenses exist separately of epidemic (e.g., genetic factors, anatomic barriers, nonspecific inhibitors in body fluids, and also phagocytosis). Others (e.g., fever, inflammation, and interferon) are produced by the organize in response to infection. All nonspecific defenses begin to act prior to the particular defense responses develop and can potentiate some of the developed immune effector mechanisms.

The reality that viruses replicate intracellularly and also the ability of part viruses to spread out by inducing cell blend partly defend viruses versus such extracellular defenses as neutralizing antibody, phagocytosis, and also nonspecific inhibitors. However, since they replicate in ~ the cell, viruses are fragile to intracellular alterations resulted in by hold responses come infection. Nonspecific responses that transform the intracellular environment incorporate fever, inflammation, and also interferon.

These many defenses role with an excellent complexity due to the fact that of their interactions with one another. This complexity is compounded by the varying effectiveness of the defenses that results from the diversity the viruses, hosts, and sites and stages the infection.


Anatomic Barriers

Anatomic barriers to viruses exist in ~ the human body surfaces and within the body. At the human body surfaces, the dead cells of the epidermis and also any live cells that may absence viral receptors stand up to virus penetration and also do no permit virus replication. However, this barrier is quickly breached, for example, by pet bites (rabies virus), insect bites (togaviruses), and minor traumas (wart virus). In ~ mucosal surfaces, just the mucus layer stands in between invading virus and live cells. The mucus layer creates a physical barrier that entraps international particles and carries them the end of the body; it additionally contains nonspecific inhibitors (see adhering to section). The mucus obstacle is not absolute, however, because sufficient quantities of numerous viruses can overwhelm it and also infect by this route. In fact, many viruses use mucous surfaces as the portal of entry and initial replication site.

Within the body, anatomic obstacles to virus spread out are formed by the class of endothelial cells that separates blood from organization (e.g., the bloodbrain barrier). Under common conditions, these barriers have a low permeability for viruses unless the virus have the right to penetrate them by replicating in the capillary endothelial cells or in turn around leukocytes. These internal barriers may explain, in part, the high level that viremia forced to epidemic organs such together the brain, placenta, and also lungs.


Nonspecific Inhibitors

A variety of viral inhibitors take place naturally in many body fluids and tissues. They differ chemically (lipids, polysaccharides, proteins, lipoproteins, and glycoproteins) and in the level of viral inhibition and varieties of viruses affected. Part inhibitors are pertained to the famous receptors the the cell surface, however most space of unknown origin. Countless inhibitors action by avoiding virus from it is registered to cells, others by directly inactivating virus, and a few by inhibiting virus replication. In the cradle tract, some vulnerable viruses room inactivated through acid, bile salts, and also enzymes. Whereas most inhibitors block only one or a few viruses, some have actually a wide antiviral spectrum. Back the efficiency of the inhibitors has actually not been totally established in vivo, their importance as organize defenses is said by your antiviral activity in tissue society and in vivo and also by the direct correlation in between the level of virulence of part viruses and also their degree of resistance to details inhibitors. Examples are the serum and mucus inhibitors that influenza viruses throughout experimental infections. However, also sensitive viruses might overwhelm this inhibitors when the infecting sheep of virus is saturated high. Therefore, the existence of this inhibitors may explain the fairly high sheep of virus compelled to initiate infection in vivo, contrasted with the dose necessary in cell cultures.


Phagocytosis

The minimal information accessible suggests that phagocytosis is much less effective against viral epidemic than versus bacterial infections. However, couple of of the factors that manage uptake the virions or infected cells by phagocytes and also their digestion by lysosomal enzymes have actually been studied systemically. Various viruses are influenced differently by the assorted phagocytic cells. Part viruses are not engulfed, vice versa, others space engulfed however may no be inactivated. In fact, part viruses, such as person immunodeficiency virus (HIV), may also multiply in the phagocytes (e.g., macrophages), which may serve as a persistent reservoir the virus (Fig. 49-1). The virulence of number of strains of HIV and herpesviruses correlates with their capacity to main point in macrophages. Infected macrophages may bring virus throughout the blood-brain barrier. Interestingly, cytomegalovirus has been report to replicate in granulocytes. Macrophages seem to be more effective versus viruses than space granulocytes, and also some viruses seem to be much more susceptible come phagocytosis than others. Macrophages and also polymorphonuclear leukocytes have the right to afford necessary protection by markedly to reduce the viremia led to by virus strains vulnerable to phagocytosis.


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Viruses might stimulate macrophages to produce monokines, which deserve to reduce viral multiplication. For example, macrophage-produced alpha interferon (IFN-α) inhibits viral multiplication both straight and additionally indirectly by activating herbal killer cells. Interleukin 1 (IL-1), developed by macrophages, deserve to interfere through viral multiplication in a variety of ways: (1) through inducing T lymphocytes to create interleukin-2, which consequently induces gamma interferon (IFN-γ), which can 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, which inhibits viral replication; (4) by improving macrophage-mediated cytolysis of infected cells; and also (5) through inducing manufacturing of tumor necrosis element (TNF), i beg your pardon inhibits virus multiplication both directly and also indirectly through inducing interferon and other cytokines and also augmenting inflammation, phagocytosis and also cytotoxic activity. Therefore, relying on the situation, macrophages acting as phagocytes may reduce the number of viruses, assist spread the infection, augment or depress immune defenses, or have tiny effect.


Fever

Viral replication is influenced strongly through temperature. Fever can be induced throughout viral infection by at the very least three elevation endogenous pyrogens: interleukins-1 and 6, interferon, prostaglandin E2, and also tumor necrosis factor. Even a usual increase have the right to cause strong inhibition: a temperature climb from 37°C come 38°C significantly decreases the productivity of plenty of viruses. This phenomenon has been it was observed in tissue culture as well as in countless experimental (including primate) and also natural infections. Artificial induction of heat reduces mortality in mouse infected through viruses (Fig. 49-2). Synthetic lowering of the temperature throughout infection may increase mortality, together in suckling mice infected through coxsackieviruses and also taken far from the warmth of your mother"s nest. Fever also augments the generation the cytotoxic T lymphocytes.


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Figure 49-2

Protection of mice by elevated temperature or antibody administered prior to or ~ intracerebral infection v the picornavirus EMC type.


Several observations suggest strongly that fever reduces virus multiplication during human viral infections. Retrospective studies have displayed that the incidence and severity the paralysis amongst children infected v polioviruses were significantly greater in patients treated through antipyretic medicine (e.g., aspirin) 보다 in untreated children. Also consistent v these findings is the observation that virus strains that replicate ideal at fever temperature are usually virulent, vice versa, virus strains the replicate poorly at fever temperature are usually low in virulence and also therefore frequently are offered as live virus vaccines.

Temperatures together low as 33°C space normal at human body surfaces exposed to air; viruses that infect this sites and also replicate optimally at this temperatures create only neighborhood infections that carry out not spread to deeper tissues, wherein the body temperature is higher. Because that example, rhinoviruses that cause common colds replicate optimally at 33°C come 34°C (found in generally ventilated nasal passages); however, they room inhibited in ~ 37°C (found once swelling of the edematous mucosa and secretions interrupt air flow). An exciting question is whether this temperature increase is essential for restore from coryza. The same general considerations of temperature probably use to other human viral infections such as measles, rubella, and mumps, although, unfortunately, perfect and managed studies have not to be conducted. Nevertheless, available information says that antipyretic medicine be provided conservatively.


Inflammation

Several antiviral instrument are created by the regional inflammatory response to virus-induced cell damages or to virus-stimulated mediators such as activated complement. The significant components that the inflammatory procedure are circulatory alterations, edema, leukocyte buildup and probably prostaglandins A and also J. The resulting phenomena are elevated local temperature, diminished oxygen anxiety in the connected tissues, altered cell metabolism, and also increased level of CO2 and also organic acids. All of these alterations, which happen in a cascading and interrelated fashion, substantially reduce the replication of numerous viruses. For instance, the changed energy metabolism of the infected and surrounding cells, and the accumulating lymphocytes, deserve to generate regional hyperthermia. At superficial sites wherein the temperature is typically lower, hyperthermia can also be produced by hyperemia during the early stages of inflammation. Together inflammation progresses, hyperemia i do not care passive, thereby substantially reducing blood flow and decreasing oxygen tension. Two components account because that this decrease in oxygen tension: restricted influx the erythrocytes, and also lower diffusion the oxygen with edema fluid. In turn, the lessened oxygen tension reasons less ATP production, thus reducing the energy accessible for viral synthesis and also increasing anaerobic glycolysis, which increases the build-up of CO2 and also organic acids in the tissues. These acid catabolites may decrease the neighborhood pH come levels that inhibit the replication of plenty of viruses. Local acidity also may boost by build-up and subsequent deterioration of the leukocytes in the impacted area. The is feasible that other much less well-defined factors are also far-reaching .

Therefore, the regional inflammation resulting from viral infection plainly activates numerous metabolic, physicochemical, and physiologic changes; exhilaration individually or together, these transforms interfere v virus multiplication. Although further animal and also human studies space required, this translate is supported by the finding that anti-inflammatory drugs (corticosteroids) regularly increase the severity of epidemic in animals. Therefore, this drugs should be offered with caution in dealing with viral diseases.


Viral Interference

Generally, infection by one virus renders host cells resistant to other, superinfecting viruses. This phenomenon, dubbed viral interference, occurs frequently in cell cultures and in animals (including humans). Return interference occurs between most viruses, it may be restricted to homologous viruses under certain conditions. 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 control). Similar interference may an outcome from competition in between defective (nonmultiplying) and infective viruses that might be developed concurrently. Another form of interference—the most important form in natural infections—is directed by the hold cells themselves. These infected cells may respond to viral infection by developing interferon proteins, which have the right to react v uninfected cells to render lock resistant to epidemic by a wide selection of viruses.


Interferon

The important function played through interferon together a defense system is clearly documented by three types of experimental and clinical observations: (1) for plenty of viral infections, a solid correlation has been established in between interferon production and natural recovery; (2) inhibition the interferon production or activity enhances the severity that infection; and (3) treatment through interferon protects against infection. In addition, the interferon system is just one of the earliest showing up of known hold defenses, becoming operative within hrs of infection.Figure 49-3 to compare the at an early stage production of interferon through the level of antibody during experimental epidemic of human beings with influenza virus. Clinical studies of interferon and also its inducers have shown protection against details viruses, consisting of hepatitis B and also C viruses, papovaviruses, rhinoviruses, and also herpes simplex virus.


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Figure 49-3

Production the virus, interferon, and also antibody during experimental epidemic of people with influenza wild-type virus. Nonspecific defenses incorporate anatomic barriers, inhibitors, phagocytosis, fever, inflammation, and also IFN. Certain defenses encompass antibody (more...)


Although interferon was very first recognized together an extremely potent antiviral agent, the was uncovered subsequently to impact other critical cell and body functions. For example, it may improve killing through granulocytes, macrophages, organic killer (NK) cells, and cytotoxic lymphocytes and influence the humoral immune response and the expression of cell membrane antigens and receptors. That may also lyse or inhibit the department of specific cells, influence cell differentiation, and also cross-activate hormone features such together those of epinephrine and also adrenocorticotropin (ACTH). The result of this modulations might influence countless viral infections.


Interferon Production and also Types

Interferon is developed de novo by moving protein synthesis. The three varieties (alpha, beta, and also gamma) different both structurally and antigenically and have molecular weights ranging from 16,000 to 45,000. Interferons space secreted through the cell right into the extracellular fluids (Fig. 49-4). Usually, virus-induced interferon is created at about the very same time as the viral progeny are released by the infected cell, hence protecting neighboring cells native the dispersing virus.


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Figure 49-4

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


The three known types of interferon are induced by various stimuli. Beta interferon is induced through viral and also other international nucleic acids in most body cells (fibroblasts, epithelial cells, and macrophages). This induction device is shown inFigure 49-4 and the top part ofFigure 49-5.


Figure 49-5

Cellular occasions of the induction, production, and action of interferon. Inducers that interferon react with cells to boring the interferon gene(s) (A). This leads to the production of mRNA for interferon (B). The mRNA is interpreted into the interferon (more...)


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

Gamma interferon is created (along with various other lymphokines) by T lymphocytes induced by foreign antigens come which the T lymphocytes have actually been presensitized (Fig. 49-4). Mitogens because that T cells might mimic this induction. Gamma interferon has several unexplained properties: (1 ) that exerts greater immunomodulatory activity, including activation the macrophages, than the other interferons; (2) that exerts higher lytic results than the various other interferons; (3) the potentiates the action of various other interferons; (4) it activates cells by a mechanism substantially different from the of the various other interferons; and also (5) it inhibits intracellular microorganisms other than viruses (e.g., rickettsia).

The 24 gene that code for interferons alpha and the solitary gene for beta in humans, are located in surrounding positions ~ above chromosome 9. The only gene for interferon gamma is discovered on chromosome 12. The gene for interferons alpha and also beta exhibit far-ranging homology but not through interferon gamma.

Genes because that interferon alpha may be distinguished into two distinctive clusters on the basis of the degree of homology. As a consequence, interferon alpha comprises two family members of proteins, at least 14 of i m sorry belong to the alpha-1 form and 2 to the alpha-2 form (omega and tau).

Also, interferon occurs without apparent stimulation in the plasma that patients through autoimmune conditions (such together rheumatoid arthritis, disseminated lupus erythematosus and pemphigus) and also in patients with advanced HIV infection. In these cases, an interferon antigenically similar to interferon alpha is present but which, unlike the latter, is partially inactivated at pH 2 (acid-labile interferon alpha). This interferon is a synergistic mix of interferons alpha (acid stable) and gamma (acid labile). Consequently, acid therapy reduces the interferon task by inactivating the synergistic interferon gamma.


Mechanism that Action

Interferon does no inactivate viruses directly. Instead, it stays clear of viral replication in surrounding cells by reacting with certain receptors on the cell membranes to derepress cellular gene that encode intracellular effector antiviral proteins, which need to be synthesized before virus replication have the right to be inhibited (Figs. 49-5 and49-6). Alpha and beta interferons both tie to the same type of membrane receptor; gamma interferon binding to a different receptor. The antiviral proteins most likely inhibit famous multiplication by inhibiting the synthesis of crucial viral proteins, but alternate or extr inhibitory instrument (e.g, inhibition the transcription and also viral release) also occur. Viral protein synthesis might be inhibited by numerous biochemical alterations that cells, i m sorry may, in theory, inhibit viral replication in ~ the different steps displayed inFigure 49-6.


It has actually been displayed that the antiviral state may be transferred from interferon-treated cells to surrounding untreated cell without the ongoing presence that interferon (Fig. 49-4); this transfer mechanism may additional amplify and spread the activity of the interferon system.

The interferon system is nonspecific in two ways: (1) various viral stimuli induce the same type of interferon, and (2) the same type of interferon inhibits miscellaneous viruses. ~ above the other hand, the interferon molecule is mostly particular in its activity for the animal species in which it to be induced: interferon produced by pets or humans generally stimulates antiviral task only in cells of the very same or very closely related families (e.g., person interferon protects human and also monkey cells, yet not chicken cells).


Interferon throughout Natural Infection

The importance of interferon in the solution to particular natural virus epidemic varies. Lot depends top top the effectiveness of the virus in stimulating interferon production and also on that is susceptibility to the antiviral activity of interferon. Interferon protects hard tissues during virus infection; that is likewise disseminated v the bloodstream throughout viremia, thereby protecting distant organs against the spreading infection. Cell protected against viral replication may get rid of virus through degrading the virus genome (Fig. 49-7).


Medical Applications

Interferons have actually been approved in several countries for treatment of viral infections (papillomas and also condylomata, herpes simplex, and also hepatitis B and C) and cancers (hairy cell leukemia, chronic myelogenous leukemia, non-Hodgkin"s lymphomas, and also Kaposi"s sarcoma in AIDS patients). Clinical trials likewise have displayed effectiveness against cryoglobulinemia and thrombocytosis and also maintenance of remission in lot of myeloma. Interferon beta has received governmental approval for therapy of relapsing lot of sclerosis and also interferon gamma because that chronic granulomatous disease. Studies of efficiency in other viral infections and cancers room continuing, as space studies through substances capable of inducing endogenous interferon.


Conclusion

In conclusion, separation, personal, instance defense mechanisms assume roles of varying prominence during various viral infections; in most cases, the recovery procedure is probably brought out by the simultaneous or sequential activity of number of mechanisms. The existence of multiple defenses helps describe why suppression that one or numerous mechanisms walk not totally abrogate host resistance to famous infections; however, disability of organize defenses by medicines used for symptomatic relief of viral infections might lead to an ext severe illness. For example, aspirin and corticosteroids alleviate the nonspecific defenses. Therefore, the well-established principle of the ancient physician—“primum non nocere” (primarily perform not harm)—is still valid.


Baron S: mechanisms of restore from viral infection. In: blacksmith KM; Lauffer MA (eds) advancements in Virus Research. Brand-new York: scholastic 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.