These inapparent infections have great epidemiologic importance: Many factors affect pathogenic mechanisms. An early determinant is the extent to which body tissues and organs are accessible to the virus. Accessibility is influenced by physical barriers such as mucus and tissue barriers , by the distance to be traversed within the body, and by natural defense mechanisms. If the virus reaches an organ, infection occurs only if cells capable of supporting virus replication are present. Cellular susceptibility requires a cell surface attachment site receptor for the virions and also an intracellular environment that permits virus replication and release.
Even if virus initiates infection in a susceptible organ, replication of sufficient virus to cause disease may be prevented by host defenses see Chs. Other factors that determine whether infection and disease occur are the many virulence characteristics of the infecting virus. To cause disease, the infecting virus must be able to overcome the inhibitory effects of physical barriers, distance, host defenses, and differing cellular susceptibilities to infection.
Viral Pathogenesis
The inhibitory effects are genetically controlled and therefore may vary among individuals and races. Virulence characteristics enable the virus to initiate infection, spread in the body, and replicate to large enough numbers to impair the target organ. These factors include the ability to replicate under certain circumstances during inflammation, during the febrile response, in migratory cells, and in the presence of natural body inhibitors and interferon.
Extremely virulent strains often occur within virus populations. Occasionally, these strains become dominant as a result of unusual selective pressures see Ch. The viral proteins and genes responsible for specific virulence functions are only just beginning to be identified. Fortunately for the survival of humans and animals and hence for the infecting virus , most natural selective pressures favor the dominance of less virulent strains. Because these strains do not cause severe disease or death, their replication and transmission are not impaired by an incapacitated host.
Mild or inapparent infections can result from absence of one or more virulence factors.
For example, a virus that has all the virulence characteristics except the ability to multiply at elevated temperatures is arrested at the febrile stage of infection and causes a milder disease than its totally virulent counterpart. Live virus vaccines are composed of viruses deficient in one or more virulence factors; they cause only inapparent infections and yet are able to replicate sufficiently to induce immunity. The occurrence of spontaneous or induced mutations in viral genetic material may alter the pathogenesis of the induced disease, e. These mutations can be of particular importance with the development of drug resistant strains of virus.
Disease does not always follow successful virus replication in the target organ. Disease occurs only if the virus replicates sufficiently to damage essential cells directly, to cause the release of toxic substances from infected tissues, to damage cellular genes or to damage organ function indirectly as a result of the host immune response to the presence of virus antigens.
As a group, viruses use all conceivable portals of entry, mechanisms of spread, target organs, and sites of excretion. This abundance of possibilities is not surprising considering the astronomic numbers of viruses and their variants see Ch. Direct cell damage and death may result from disruption of cellular macromolecular synthesis by the infecting virus.
Also, viruses cannot synthesize their genetic and structural components, and so they rely almost exclusively on the host cell for these functions.
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Their parasitic replication therefore robs the host cell of energy and macromolecular components, severely impairing the host's ability to function and often resulting in cell death and disease. Pathogenesis at the cellular level can be viewed as a process that occurs in progressive stages leading to cellular disease. As noted above, an essential aspect of viral pathogenesis at the cellular level is the competition between the synthetic needs of the virus and those of the host cell.
Since viruses must use the cell's machinery to synthesize their own nucleic acids and proteins, they have evolved various mechanisms to subvert the cell's normal functions to those required for production of viral macromolecules and eventually viral progeny. The function of some of the viral genetic elements associated with virulence may be related to providing conditions in which the synthetic needs of the virus compete effectively for a limited supply of cellular macromolecule components and synthetic machinery, such as ribosomes.
Damage of cells by replicating virus and damage by the immune response are considered further in Chapters 44 and 50 , respectively. Most viruses have an affinity for specific tissues; that is, they display tissue specificity or tropism. This specificity is determined by selective susceptibility of cells, physical barriers, local temperature and pH, and host defenses. Many examples of viral tissue tropism are known. Polioviruses selectively infect and destroy certain nerve cells, which have a higher concentration of surface receptors for polioviruses than do virus-resistant cells.
Rhinoviruses multiply exclusively in the upper respiratory tract because they are adapted to multiply best at low temperature and pH and high oxygen tension. Enteroviruses can multiply in the intestine, partly because they resist inactivation by digestive enzymes, bile, and acid. The cell receptors for some viruses have been identified.
Viral pathogenesis
Rabies virus uses the acetylcholine receptor present on neurons as a receptor, and hepatitis B virus binds to polymerized albumin receptors found on liver cells. Similarly, Epstein-Barr virus uses complement CD21 receptors on B lymphocytes, and human immunodeficiency virus uses the CD4 molecules present on T lymphocytes as specific receptors. Viral tropism is also dictated in part by the presence of specific cell transcription factors that require enhancer sequences within the viral genome.
Recently, enhancer sequences have been shown to participate in the pathogenesis of certain viral infections. Enhancer sequences within the long terminal repeat LTR regions of Moloney murine leukemia retrovirus are active in certain host tissues.
In addition, JV papovavirus appears to have an enhancer sequence that is active specifically in oligodendroglia cells, and hepatitis B virus enhancer activity is most active in hepatocytes. Tissue tropism is considered further in Chapter Viruses are carried to the body by all possible routes air, food, bites, and any contaminated object.
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Similarly, all possible sites of implantation all body surfaces and internal sites reached by mechanical penetration may be used. The frequency of implantation is greatest where virus contacts living cells directly in the respiratory tract, in the alimentary tract, in the genital tract, and subcutaneously. With some viruses, implantation in the fetus may occur at the time of fertilization through infected germ cells, as well as later in gestation via the placenta, or at birth.
Even at the earliest stage of pathogenesis implantation , certain variables may influence the final outcome of the infection. For example, the dose, infectivity, and virulence of virus implanted and the location of implantation may determine whether the infection will be inapparent subclinical or will cause mild, severe, or lethal disease. Successful implantation may be followed by local replication and local spread of virus Fig. Virus that replicates within the initially infected cell may spread to adjacent cells extracellularly or intracellularly.
Extracellular spread occurs by release of virus into the extracellular fluid and subsequent infection of the adjacent cell. Intracellular spread occurs by fusion of infected cells with adjacent, uninfected cells or by way of cytoplasmic bridges between cells. Most viruses spread extracellularly, but herpesviruses, paramyxoviruses, and poxviruses may spread through both intracellular and extra cellular routes. Intracellular spread provides virus with a partially protected environment because the antibody defense does not penetrate cell membranes.
Virus spread during localized infection. Numbers indicate sequence of events. Spread to cells beyond adjacent cells may occur through the liquid spaces within the local site e. Also, infected migratory cells such as lymphocytes and macrophages may spread the virus within local tissue. Establishment of infection at the portal of entry may be followed by continued local virus multiplication, leading to localized virus shedding and localized disease.
In this way, local sites of implantation also are target organs and sites of shedding in many infections Table Respiratory tract infections that fall into this category include influenza, the common cold, and parainfluenza virus infections. Alimentary tract infections caused by several gastroenteritis viruses e. Localized skin infections of this type include warts, cowpox, and molluscum contagiosum. Localized infections may spread over body surfaces to infect distant surfaces.
An example of this is the picornavirus epidemic conjunctivitis shown in Figure ; in the absence of viremia, virus spreads directly from the eye site of implantation to the pharynx and intestine.
Other viruses may spread internally to distant target organs and sites of excretion disseminated infection. A third category of viruses may cause both local and disseminated disease, as in herpes simplex and measles. Pathogenesis of Selected Virus Infection: Spread of picornavirus over body surfaces from eye to pharynx and intestine during natural infection.
Local neutralizing antibody activity is shown. Early appearing antiviral activity in human tears during more At the portal of entry, multiplying virus contacts pathways to the blood and peripheral nerves, the principal routes of widespread dissemination through the body. The most common route of systemic spread of virus involves the circulation Fig. Viruses such as those causing poliomyelitis, smallpox, and measles disseminate through the blood after an initial period of replication at the portal of entry the alimentary and respiratory tracts , where the infection often causes no significant symptoms or signs of illness because the virus kills cells that are expendable and easily replaced.
Virus progeny diffuse through the afferent lymphatics to the lymphoid tissue and then through the efferent lymphatics to infect cells in close contact with the bloodstream e. This initial spread may result in a brief primary viremia. Subsequent release of virus directly into the bloodstream induces a secondary viremia, which usually lasts several days and puts the virus in contact with the capillary system of all body tissues. Virus may enter the target organ from the capillaries by replicating within a capillary endothelial cell or fixed macrophage and then being released on the target organ side of the capillary.
Virus may also diffuse through small gaps in the capillary endothelium or penetrate the capillary wall through an infected, migrating leukocyte. The virus may then replicate and spread within the target organ or site of excretion by the same mechanisms as for local dissemination at the portal of entry. Disease occurs if the virus replicates in a sufficient number of essential cells and destroys them.
For example, in poliomyelitis the central nervous system is the target organ, whereas the alimentary tract is both the portal of entry and the site of shedding. In some situations, the target organ and site of shedding may be the same. Virus spread through bloodstream during a generalized infection. Pathogenesis of Selected Virus Infections: Dissemination through the nerves is less common than bloodstream dissemination, but is the means of spread in a number of important diseases Fig. This mechanism occurs in rabies virus, herpesvirus, and, occasionally, poliomyelitis virus infections.
Viral pathogenesis - an overview | ScienceDirect Topics
For example, rabies virus implanted by a bite from a rabid animal replicates subcutaneously and within muscular tissue to reach nerve endings. Evidence indicates that the virus spreads centrally in the neurites axons and dendrites and perineural cells, where virus is shielded from antibody. This nerve route leads rabies virus to the central nervous system, where disease originates. Rabies virus then spreads centrifugally through the nerves to reach the salivary glands, the site of shedding.
Table shows other examples of nerve spread. Virus spread through nerves during a generalized infection. During most virus infections, no signs or symptoms of disease occur through the stage of virus dissemination. Thus, the incubation period the time between exposure to virus and onset of disease extends from the time of implantation through the phase of dissemination, ending when virus replication in the target organs causes disease.
Occasionally, mild fever and malaise occur during viremia, but they often are transient and have little diagnostic value. The incubation period tends to be brief 1 to 3 days in infections in which virus travels only a short distance to reach the target organ i. Conversely, incubation periods in generalized infections are longer because of the stepwise fashion by which the virus moves through the body before reaching the target organs.
Other factors also may influence the incubation period. Viral pathogenesis is the study of how biological viruses cause diseases in their target hosts , usually carried out at the cellular or molecular level. It is a specialized field of study in virology. There are several factors that affect pathogenic mechanisms.
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Some of these factors include virulence characteristics of the virus that is infecting. In order to cause disease, the virus must overpower several inhibitory effects present in the host. Some of the inhibitory effects include distance, physical barriers, host defenses, and conflicting cellular susceptibilities. These inhibitory effects may differ among individuals and different races due to the inhibitory effects being genetically controlled. Three requirements must be satisfied to ensure a successful infection of a host. There must be sufficient virus available to initiate the infection.
Cells at the site of infection must be accessible, susceptible, and allow the virus to enter, and the host anti-viral defense systems must be ineffective or absent. There are several mechanisms that must occur for a viral disease to develop: Viruses that travel a short distance to reach their target organ have a short incubation period. The incubation period tends to be 1 to 3 days. On the other hand, with generalized infections, the incubation period is longer because of how long it takes the virus to move throughout the body and reach the target organs.
There are several other factors that affect the incubation period.