MM 526-541
1. To contrast the mechanisms of viral pathogenicity with those of bacterial pathogenicity.
2. To develop the concept of the target organ in viral pathogenicity.
3. To stress the role of immune mechanisms in virus-induced cell damage.
4. To define the role of viruses in teratology.
Specific educational objectives (terms and concepts upon which you will be tested)
Generally, the virulence of pathogenic bacteria is directly related to the ability of the organism to produce one or more toxins. However, the virulence of viruses is not well defined. A number of factors contribute to the virulence (pathogenicity) of a particular strain of virus.
A. Ability to enter the cell
B. Ability to grow within the cell
C. Ability to combat host defense mechanisms
D. Ability to produce temporary or permanent damage in the host via:
1. Cell lysis
2. Production of toxic substances
3. Cell transformation
4. Induction of formation of substances which are not specified by the viral genome, but are apparently cellular products normally not produced by the cell.
5. Induction of structural alterations in the host cell
(a) Nuclear (including chromosomal)
(b) Cytoplasmic
Some viruses enter host tissues directly by trauma or insect bite, but most infections start on the mucous membranes of the respiratory and alimentary tracts. To initiate infection, virus particles must first survive on these mucous-covered membranes in the presence of viral and non-viral commensals. Subsequently, to replicate, the virus must enter host cells either in the mucous membrane itself or in tissues farther afield after penetration through the surface membrane. Replication in mucous membrane cells can produce the disease effects directly as in respiratory diseases, but sometimes it provides a staging post for subsequent damaging replication in another site, e.g., polio virus replicates first in the alimentary tract cells and ultimately in anterior horn cells of the spinal cord.
The host anti-viral defense mechanisms include:
A. Non-specific host defense mechanisms
1. Humoral factors
(a) Low pH of inflammatory exudates
(b) Enzymes
(c) Mucous
(d) Virocidins
2. Cellular factors
(a) Nucleases
(b) Proteases
(c) Interferon
B. Specific host defense mechanisms
1. Antibody
2. Activated phagocytes
How virulent viruses overcome these non-specific and specific virus inhibitors is unknown. They do bypass these inhibitors and infect the mucosal cells in certain diseases (influenza, common cold). Other viruses pass through the mucosa without establishing infection in the membrane itself, but infect other body tissues.
Although ability to replicate in host tissues is not the only factor in virus virulence, it is essential, and the more rapid the rate of replication, the more likely the success of the virus in producing its disease syndrome. Ability to proliferate in vivo depends on an inherent ability to replicate in the biochemical conditions of the host tissues, coupled with a capacity to resist or not to stimulate host defense mechanisms which would otherwise kill or remove them. The ability of a virus to replicate in a particular cell depends on inherent features of the cell as well as the virus. These features can be involved in one or more stages of replication:
A. Attachment
B. Penetration
C. Uncoating
D. Provision of energy and precursors of low-molecular-weight compounds
E. Nucleic acid and protein synthesis
F. Assembly
G. Release
Assuming that a virus can enter a cell and complete its normal replication cycle, what are some specific temporary or permanent damages incurred by the cell? The most obvious is cell lysis. This may occur due to a physical internal pressure exerted by the multiplying virus. The cell becomes filled with virus and merely bursts. This is common with bacterial viruses, but not with animal viruses. With animal viruses, cell lysis is usually the result of one of four types of allergic reactions:
1. Type I. IgE antibodies fixed to mast cells react with the complete virus or with viral components, triggering release of histamine and activation of slow reacting substance (SRS-A) and eosinophil chemotactic factor (ECF-A). These act on blood vessels, smooth muscle and secreting glands to give the typical anaphylactic type reaction. Allergy to viruses usually results in a very localized anaphylactic reaction. Furthermore this viral-mediated reaction is limited to a few virus species.
2. Type II. IgG and/or IgM antibodies are involved in this reaction. The effects can be of two types:
(a) The virus (or viral component) - complement - antibody complex is fixed to a cell, usually an erythrocyte or leukocyte or platelet, resulting in complement-dependent cell lysis. This is the pathogenic mechanism in many viral diseases where anemia is one of the clinical manifestations.
(b) A virus component, commonly the capsid protein, is expressed on the surface of the infected cell. Antibody and complement bind to this infected cell and cause a lysis of that cell. This is thought to be the major mechanism of viral-induced cell lysis.
3. Type III. IgG and/or IgM antibodies form complexes with viral antigen and complement, generating neutrophil chemotactic factors, with resultant local tissue inflammation and destruction. Although much rarer, some viral diseases may result in a generalized rather than localized tissue destruction. This type of disease is a multi-system complement-dependent vasculitis in which immune complexes are deposited along the endothelial surfaces of blood vessels, stimulating inflammation and vascular wall damage.
The III reactions are known as Arthus-type reactions. The classical symptoms of this type of hypersensitivity are edema, polymorphonuclear leukocyte infiltration and hemorrhage. These are followed by secondary necrosis which reaches a maximum in 8-24 hours. This type of hypersensitivity is due to precipitating antibody only, and requires a large amount of antibody. The antibody is not fixed to the tissues. Histamine does not duplicate the reaction and antihistamines do not suppress the reaction.
4. Type IV. This type of allergic reaction does NOT involve antibody. Sensitized T-lymphocytes react directly with viral antigen, usually that antigen expressed on the surface of an infected cell, producing inflammation through the action of lymphokines. This leads to lysis of the infected cell. This is a delayed-type hypersensitivity which results in the Zinkernagel-Dougherty phenomenon. This is probably the second most common allergic reaction to viruses.
During the course of virus replication, many viral components as well as by-products of viral replication accumulate in the cell. These are often cytotoxic (e.g., Vaccinia virus in HeLa cells). The molecular mechanism of these toxins is not known in most cases. Only gross morphological defects can be observed generally. Some examples are:
1. Cytotoxicity of preformed viral parts. e.g., Sendoi virus, Newcastle disease virus, measles virus and SV5 produce rapid polykaryocytosis (fusion of chromosomes).
2. Herpesvirus components produce syncytia (multi-nucleated protoplasmic mass, seemingly an aggregation of numerous cells without a regular cell outline).
3. Penton of adenovirus causes host cell rounding and cell detachment from glass.
4. A double-stranded RNA from enterovirus causes rapid death, without the production of infectious virus, of cells susceptible and unsusceptible to enterovirus infection.
5. The fiber antigen of the adenovirus capsid inhibits RNA, DNA and protein synthesis.
6. Large quantities of some viruses, such as influenza virus and poxviruses, cause rapid toxic effects in some animals.
Certain viruses have the ability to enter a cell and follow one of two alternative courses. They either multiply in a normal manner and are eventually released from the cell, or they may be dormant in the cell and eventually transform the cell into a malignant cell. It is believed that the transformation process involves the integration of viral nucleic acid into the host chromosome. When this happens, the cell achieves certain characteristics of malignant cells.
Since many viruses are known to replicate in cells of the lymphoreticular system, it is possible that these viruses can affect the immune system. Viruses or virus-like particles have been found in the thymus, lymph nodes, spleen, bone marrow, stem cells, plasma cells, lymphocytes, macrophages, monocytes, polymorphonuclear leukocytes and Kupffer cells. The nature and extent of the immunologic alteration depends on the organ or cell type infected and the species of virus causing the infection. These effects have been demonstrated in each of the following systems.
1. Humoral Immunity
(a) In animal model systems the Moloney leukemia virus, Friend leukemia virus, Ranscher leukemia virus and the avian leukosis virus all cause a depression of the synthesis of immunoglobulins of the IgM and IgG classes. Although human leukemia has not yet been shown to be of viral etiology, the analogy with animal systems is strengthened by the fact that human leukemia victims do have a reduced ability to synthesize immunoglobulins.
(b) Viruses which do not produce leukemia but infect lymphoid tissue also decrease the immune response of the host. Again in animal model systems, the lymphocytic choriomeningitis virus, the Argentinian hemorrhagic fever virus and the Aleutian mink disease virus all cause a lessened antibody (IgM and IgG) response to a variety of antigens. Depression of the immune response is greatest in adults, temporary in neonates and absent in chronic virus infections.
(c) Both leukemia and lymphoma viruses also decrease the ability of an animal to undergo anaphylaxis. This is thought to be due to a reduced synthesis of IgE.
Many theories have been proposed to explain how viruses depress immune function. Since these are only theories at the present, only the more common ones are worth mentioning.
(a) Viruses alter the uptake and processing of antigens.
(b) Viruses depress cellular protein (antibody) synthesis.
(c) Viruses destroy antibody-producing cells.
(d) Viruses increase immunoglobulin catabolism.
2. Cellular immunity
(a) Again, in animal systems, it has been shown that both leukemia viruses and non-leukemia viruses can either prevent or ameliorate homograft rejection across weak histocompatibility barriers.
(b) Many viruses promote the growth of tumors which would normally be rejected by the host's cellular immune mechanisms.
(c) More relevant to human medicine is the fact that infection with measles virus, influenza virus, chickenpox virus, polio virus or rubella virus causes a depression of delayed hypersensitivity as measured by skin reaction to tuberculin.
The major theory explaining these phenomena relates the reduced cellular immunity to a depressed ability to undergo lymphocyte blast transformation.
3. Reticuloendothelial system and phagocytosis
(a) In animal studies, infection with either lactic dehydrogenase virus, ectromelia virus, hepatitis virus or lymphocytic choriomeningitis virus causes a slower clearance of carbon particles from the circulatory system.
(b) Infection of animals with Venezuelan equine encephalitis virus, Friend leukemia virus or Moloney leukemia virus augments clearance of carbon particles.
(c) Infection of human polymorphonuclear leukocytes with mumps virus, influenza virus or Coxsackie virus decreases the ability of these cells to engulf bacteria.
No theories have been proposed to account for the effects of viruses on the RES.
Virus-infected cells, at times, will produce compounds coded for by the host DNA, but which are not normally produced by the host. These are often cytotoxic at relatively high concentrations. Other host compounds which are normally found in low concentration may be produced in higher concentration during a virus infection. Again, this high concentration may be cytotoxic. Some virus-induced products release autolytic enzymes from the cells own lysosomes.
Viruses can induce structural alterations in the host cell's cytoplasm and nucleus. These are often of diagnostic importance.
1. Cytoplasmic changes
(a) Small non-enveloped RNA viruses produce a large eosinophilic mass which displaces the nucleus. There is a generalized increase in basophilia. The cytoplasm appears to bubble at the cell periphery.
(b) Myxoviruses (influenza, fowl, plague) cause cytoplasmic vacuolization, contraction and degeneration. "Buds" appear on cell surface.
(c) Myxoviruses (mumps, NDV) cause eosinophilia and Feulgen-negative cytoplasmic inclusions.
(d) Reovirus and measles virus cause eosinophilia.
(e) Poxviruses cause formation of Feulgen-positive cytoplasmic inclusions which contain virions.
(f) Herpesvirus causes vacuolization.
2. Nuclear changes
(a) Pyknosis (nucleus pushed to eccentric position in cell); e.g., small non-enveloped RNA viruses, influenza virus, fowl plague virus, mumps virus, NDV.
(b) Nuclear inclusion (bodies in the nucleus); e.g., herpesvirus, adenovirus.
(c) Margination and coarsening of chromatin; e.g. herpesvirus, poxvirus.
(d) Polykaryocytosis (many nuclei in the same cytoplasmic field); e.g., herpesvirus and measles virus.
(e) Formation of chromosomal bridges. e.g. herpesvirus and polyoma virus.
(f) Formation of chromosomal breaks. If both chromatids are broken, the break is complete. If only one chromatid is broken, the break is partial. A second important characteristic that has been used in the classification of chromosomal breaks is dependent on whether or not healing or reunion has occurred in the broken ends. If no reunion has occurred, then there is a gap or a terminal deletion. If reunion occurs in other than the original position, then a structural rearrangement is the result.
(g) Structural rearrangements of chromosome:
(1) Quadriradials
(2) Dicentric chromosomes
(3) Interlocking ring chromosomes
(4) Dicentric chromosome resulting from involvement of only one chromatid
(5) Chromosome arms or branches
(h) Defects in the mitrolic apparatus (alteration of the spindle and mitotic mechanism). These alterations produce changes in chromosome number and are of three types:
(1) Changes in spindle mechanism. This is seen in virus-induced syncytia, where various nuclear groups exhibit some degree of mitotic syndromy. These synchronized metaphase plates share common spindles and polar groups, and by virtue of this become rearranged in various geometric shapes. During anaphase, chromosomes in the various metaphase plates that are sharing the same pole come together at this pole, producing new chromosomal rearrangements and changes in chromosome number in each nuclear group.
(2) Changes in mitotic mechanism. This is seen in virus-induced persistence of nucleoli during mitosis. The end result is a change in chromosome number. Normally, nucleoli disappear during mitosis and then reappear at telophase. However, in cells treated with inhibitors of DNA synthesis or infected with certain viruses, the nucleolus is visible during mitosis. The importance of the persistent nucleolus is that the nucleolus is formed at specific areas of chromosomes, the nucleolus organizer, and then it persists, it joins together and two chromatids of these chromosomes and produces separation difficulties during anaphase, which may result in nondisjunction.
(3) Induction of mitotic delay or mitotic inhibition. This is a frequently observed phenomenon in acute virus infections of cells in cultures, although it appears to be a non-specific phenomenon.
3. Membrane changes
(a) The human cell membrane is a dynamic structure continually changing in lipid and protein content during normal cellular growth and division. Viral infection of the cell often results in viral protein being incorporated into this membrane. There is also limited evidence suggesting that the lipid content is altered. These changes can lead to production of antibodies against the cell membrane and lysis of this membrane as previously discussed.
1. Most commonly viral damage to the host cell is manifested as cell lysis mediated by one or more of four types of allergic reactions.
2. Type II allergic reactions involving IgG and/or IgM are the major mechanism of viral-induced cell lysis.
3. Type IV allergic reactions not involving antibody are the second most common mechanism of viral-induced cell lysis.
4. A few species of viruses produce viral components which are toxic to the human host cell much like some products of bacteria.
5. Certain species of viruses have the ability to transform a benign cell to a malignant cell via integration of the viral nucleic acid into the human chromosome.
6. Selected species of virus have the ability to alter human immune responses (humoral and cellular) via alteration of immune cell metabolism or immune cell lysis.
7. Some species of viruses "turn on" or activate host cell genes to overproduce the gene product. This product can be cytotoxic in high concentrations.
8. A great number of viral species induce cytoplasmic and/or nuclear changes in their host cells which can be used by the pathologist in diagnosing viral infectious diseases.
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