For the determination of viral tissue tropism, we analyzed different organs and tissues of 1 NPHV-positive horse using quantitative real-time polymerase chain reaction and fluorescent in situ hydridization and detected NPHV RNA mainly in the liver and at lower amounts in other organs. Abstract Hepatitis C virus HCV has a very narrow species and tissue tropism and efficiently replicates only in humans and the chimpanzee.
Publication types Research Support, N. 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. 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. 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. 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. Spread of picornavirus over body surfaces from eye to pharynx and intestine during natural infection. Local neutralizing antibody activity is shown. 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. 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.
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.
Nevertheless, many unanswered questions remain with regard to optimal ZIKV antigens, the viral genetics of virulence, mechanisms of host restriction and immune evasion, the potential for ADE of ZIKV and DENV pathogenesis, as well as the long-term neurodevelopmental implications of congenital infection in humans. Given the exceptionally rapid pace of ZIKV research, we expect several of these questions to be answered soon. D supported this work. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.
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National Center for Biotechnology Information , U. Cell Host Microbe. Author manuscript; available in PMC Feb 8. Jonathan J. Miner 1, 2, 3 and Michael S. Michael S. Author information Copyright and License information Disclaimer.
Diamond, M. Copyright notice. The publisher's final edited version of this article is available at Cell Host Microbe. See other articles in PMC that cite the published article. Abstract Although Zika virus ZIKV was isolated approximately 70 years ago, few experimental studies had been published prior to Human-to-human transmission Unlike most other flaviviruses, a component of the spread of ZIKV may reflect its potential for human-to-human transmission.
Open in a separate window. Figure 1. ZIKV tissue and cell tropism Human studies and animal models mice and non-human primates have detected ZIKV in cells of the placenta including Hofbauer cells in vitro and in explanted human placental tissue , trophoblasts mice, non-human primates, and humans , and endothelial cells in vitro in explanted human placental tissue and in vivo in placenta of mice.
ZIKV tissue and cell tropism One potential mechanism for observed microcephaly is that ZIKV preferentially infects and triggers apoptosis in neural progenitor cells Dang et al. Figure 2. Conclusions Animal and human studies of ZIKV pathogenesis have revealed broad tissue and cell tropism for ZIKV as well as the capacity for the virus to cause severe end-organ disease in addition to placental and congenital infection.
Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med. From ZikV genome to vaccine: in silico approach for the epitope-based peptide vaccine against Zika virus envelope glycoprotein. Structural basis of potent Zika—dengue virus antibody cross-neutralization.
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