Viral affinity for specific body tissues (tropism) is determined by
cell receptors for virus,
cell transcription factors that recognize viral promoters and enhancer sequences,
ability of the cell to support virus replication,
local temperature, pH, and oxygen tension enzymes and non-specific factors in body secretions, and
digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses.
Implantation at the Portal of Entry
Virions implant onto living cells mainly via the respiratory, gastrointestinal, skin-penetrating, and genital routes although other routes can be used. The final outcome of infection may be determined by the dose and location of the virus as well as its infectivity and virulence.
Local Replication and Local Spread
Most virus types spread among cells extracellularly, but some may also spread intracellularly. Establishment of local infection may lead to localized disease and localized shedding of virus.
Dissemination from the Portal of Entry
Viremic: The most common route of systemic spread from the portal of entry is the circulation, which the virus reaches via the lymphatics. Virus may enter the target organs from the capillaries by multiplying in endothelial cells or fixed macrophages,
diffusing through gaps, and
being carried in a migrating leukocyte.
Neural: Dissemination via nerves usually occurs with rabies virus and sometimes with herpesvirus and poliovirus infections.
The incubation period is the time between exposure to virus and onset of disease. During this usually
local multiplication, and
spread (for disseminated infections) occur.
Multiplication in Target Organs
Depending on the balance between virus and host defenses, virus multiplication in the target organ may be sufficient to cause disease and death.
Although the respiratory tract, alimentary tract, urogenital tract and blood are the most frequent sites of shedding, diverse viruses may be shed at virtually every site.
Infection of the fetus as a target "organ" is special because the
virus must traverse additional physical barriers,
the early fetal immune and interferon defense systems may be immature,
transfer of the maternal defenses are partially blocked by the placenta,
the developing first-trimester fetal organs are vulnerable to infection, and
hormonal changes are taking place.
Pathogenesis is the process by which virus infection leads to disease. Pathogenic mechanisms include
implantation of the virus at a body site (the portal of entry),
replication at that site, and
then spread to and multiplication within sites (target organs) where disease or shedding of virus into the environment occurs.
Most viral infections are subclinical, suggesting that body defenses against viruses arrest most infections before disease symptoms become manifest. Knowledge of subclinical infections comes from serologic studies showing that sizeable portions of the population have specific antibodies to viruses even though the individuals have no history of disease. These inapparent infections have great epidemiologic importance: they constitute major sources for dissemination of virus through the population, and they confer immunity (see Ch. 48).
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. 49 and 50).
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 ableto overcome the inhibitory effects of physical barriers, distance, host defenses, and differing cellular susceptibilities to infection. The inhibitory effects are genetically controlled and therefore may vary among individuals and races. Virulencecharacteristics 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. 48). 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.g. HIV. 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 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. 43).
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. 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.
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. 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 44.
Sequence of Virus Spread in the Host
Implantation at Portal of Entry
Viruses are carried to the body by all possible routes (air, food, bites, and any contaminated object). 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.
Local Replication and Local Spread
Successful implantation may be followed by local replication and local spread of virus (Fig. 45-1). 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.