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.
Ability to enter the cell
Ability to grow within the cell
Ability to combat host defense mechanisms
Ability to produce temporary or permanent damage in the host via:
Production of toxic substances
Induction of formation of substances which are not specified by the viral
genome, but are apparently
cellular products normally not produced by the cell.
of structural alterations in the host cell
Nuclear (including chromosomal)
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.
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.
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:
Provision of energy
Synthesis of precursors of low molecular weight compounds
Nucleic acid and protein synthesis
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:
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.
Type II. IgG and/or IgM antibodies are involved in this reaction. The effects
can be of two types:
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
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.
Type III. IgG and/or IgM antibodies form complexes with viral antigen and
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.
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.
of toxic substances
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:
Cytotoxicity of preformed viral parts. e.g., Sendoi virus, Newcastle disease
virus, measles virus and SV5
produce rapid polykaryocytosis
(fusion of chromosomes).
Herpesvirus components produce syncytia
(multi-nucleated protoplasmic mass, seemingly an aggregation
of numerous cells without a regular cell outline).
Penton of adenovirus causes host cell rounding and cell detachment from
A double-stranded RNA from enterovirus causes rapid death, without the
production of infectious virus, of
cells susceptible and unsusceptible to enterovirus infection.
The fiber antigen of the adenovirus capsid inhibits RNA, DNA and protein
Large quantities of some viruses, such as influenza virus and poxviruses,
cause rapid toxic effects in some
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
of the immune mechanisms
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.
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
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.
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.
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.
Viruses alter the uptake and processing of antigens.
Viruses depress cellular protein (antibody) synthesis.
Viruses destroy antibody-producing cells.
Viruses increase immunoglobulin catabolism.
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
Many viruses promote the growth of tumors which would normally be rejected
by the host's cellular immune
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.
Reticuloendothelial system and phagocytosis
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
Infection of animals with Venezuelan equine encephalitis virus, Friend
leukemia virus or Moloney leukemia
virus augments clearance of carbon particles.
Infection of human polymorphonuclear leukocytes with mumps virus, influenza
virus or Coxsackie virus
decreases the ability of these cells to engulf bacteria.
theories have been proposed to account for the effects of viruses on the
of non-normal host-specified products
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.
of structural alterations in the host cell
can induce structural alterations in the host cell's cytoplasm and nucleus.
These are often of diagnostic importance.
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.
Myxoviruses (influenza, fowl, plague) cause cytoplasmic vacuolization,
contraction and degeneration.
"Buds" appear on cell surface.
Myxoviruses (mumps, NDV) cause eosinophilia and Feulgen-negative cytoplasmic
Reovirus and measles virus cause eosinophilia.
Poxviruses cause formation of Feulgen-positive cytoplasmic inclusions which
Herpesvirus causes vacuolization.
(nucleus pushed to eccentric position in cell); e.g., small non-enveloped
RNA viruses, influenza
virus, fowl plague virus, mumps virus, NDV.
Nuclear inclusion (bodies in the nucleus); e.g., herpesvirus, adenovirus.
Margination and coarsening of chromatin; e.g. herpesvirus, poxvirus.
Polykaryocytosis (many nuclei in the same cytoplasmic field); e.g., herpesvirus
and measles virus.
Formation of chromosomal bridges. e.g. herpesvirus and polyoma virus.
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
Structural rearrangements of chromosome:
Interlocking ring chromosomes
Dicentric chromosome resulting from involvement of only one chromatid
Chromosome arms or branches
Defects in the mitrolic apparatus (alteration of the spindle and mitotic
mechanism). These alterations
produce changes in chromosome number and are of three types:
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
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.
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
difficulties during anaphase, which may result in nondisjunction.
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
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.
Most commonly viral damage to the host cell is manifested as cell lysis
mediated by one or more of four types of allergic reactions.
Type II allergic reactions involving IgG and/or IgM are the major mechanism
of viral-induced cell lysis.
Type IV allergic reactions not involving antibody are the second most common
mechanism of viral-induced cell
A few species of viruses produce viral components which are toxic to the
human host cell much like some products of bacteria.
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
Selected species of virus have the ability to alter human immune responses
(humoral and cellular) via alteration of immune cell metabolism or immune
Some species of viruses "turn on" or activate host cell genes to overproduce
the gene product. This product can be cytotoxic in high concentrations.
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.