Viral Pathogenesis

OBJECTIVES
• Viral Pathogenesis
• Viral Infections
• Factors Involved in Viral Pathogenesis
• Viral pathogenesis at the cellular level
• Routes of Entry and Dissemination to
Secondary sites
• Typical secondary sites of localization
• Primary and Secondary Infection
• Cell Tropism
• Factors Involved in Termination of The
Acute Infection
• Viral Clearance or Persistence

Viral Pathogenesis
It is the process by which a
viral
infection leads to disease.
The consequences of viral
infections
depend on the interplay
between a
number of viral and host
factors.
Viruses may persist for a
long time in
the host in one of the
following forms:
Chronic infections, Latent
infections
or Slow infections:
Chronic Infections
They usually develop from
acute infections
and can last for days to months to
a lifetime.
Recovery from this infection is
rare.
People may be able to transmit
the germ to
others.
serious signs may not appear
until as long as
20 years after the infection began.
For example: hepatitis C, which
affects the
liver is a chronic viral infection.
Latent Infection
virus is present in the body,
but it
remains dormant, not causing
any overt
symptoms.
People can pass the virus on to
others.
Latent infections can also be
activated,
causing symptoms and illness to
emerge
again.
Eg: latent infection is Herpes
simplex,
which periodically flares up to
cause cold
sores before going dormant
again.
Slow infections-
These diseases have a
prolonged
incubation period (which
can be
months or years), and a
progressive
clinical course. e.g:
Human
immunodeficiency virus
Viral Virulence
• The ability of a virus to cause
disease in an
infected host
• A virulent strain causes significant
disease
• An avirulent or attenuated strain
causes no or
reduced disease
• Virulence depends on
– Dose
– Virus strain (genetics)
– Inoculation route - portal of entry
– Host factors - eg. Age SV in adult
neurons
goes persistent but is lytic in young
Viral genes that affect
virulence
may
•Affect the ability of the virus to
replicate
•Enable the virus to spread
within host or
between hosts
•Defeat host defense
mechanisms
•Produce products that are
directly toxic
Viral genes that affect
virulence
Factors Involved in Viral
Pathogenesis
Effects of viral infection on cells (Cellular Pathogenesis)
Entry into the Host

Course of Infection (Primary Replication, Systemic

Spread, Secondary
Replication)
Cell/Tissue Tropism

Cell/Tissue Damage

Host Immune Response

Virus Clearance or Persistence

Viral pathogenesis at
the
cellular level
• Cells show variety of different
responses to viral
infection depending on the
-cell type
-and the virus.
• Many viral infections cause no
apparent
morphologic or functional changes
in the cell
• When changes do occur , several
responses can
be recognized :
1-Cell death:
A cell can be directly killed by the
virus. in
most cases this is due to the
inhibition of
synthesis of cellular DNA , RNA and
protein.
2-Transformation
Some viruses can transform normal
cells into
malignant cells.
Transformation:
is an irreversible genetic process
caused by the integration of viral
DNA
into the host’s DNA.
3-Cell fusion :
infection of cells with certain viruses
causes
the cells to fuse producing giant
multinucleate
and cells. E.g. herpesviruses
paramyxoviruses
4-Cytopathic effect ( CPE) :
CPE is a catch-all term that refers to
any
of an infected visible changes in
appearance
Routes of Entry and
Dissemination to
Secondary
sites
• Common routes by which
viruses
enter the body are essentially
the
same as for bacterial
infections
through:
-Skin
- Respiratory tract
- Gastrointestinal tract
- Urogenital tract
Routes of Entry
1-skin
Introduction through the skin
usually a break
in the surface of the skin from an
abrasion or
cut , or by inoculation of the agent
by an insect
, animal bite , or needle
2-Respiratory tract: those viruses
that enter the
body via the respiratory tract and
remain
localized produce symptoms that
primarily in
the respiratory passages causing
common cold
(Rhinoviruses)
-other inhaled viruses spread
systemically after
the primary infection , and produce
a
characteristic disease due to the
infection of
Routes of Entry
(cont’d)
3-Gastrointestinal tract
• Viruses infecting via the GI tract
follow
characteristic “fecal-oral”
transmission pattern
,those viruses that remain localized
in the cells
of the GI tract may cause symptoms
such as
diarrheal disease, for example
,enteric
adenoviruses or rotaviruses
• Many viral infections that remain
localized in
the GI tract are aysmptomatic
• Some viruses that infect via the GI
tract enter
the lymphatic system and the blood,
then can
cause symptomatic disease unrelated
to the GI
4-Genital tract
• Viruses infecting by this route are
transmitted
primarily during sexual contact .
• spread of the virus can affect
nongenital tissues,
tissues, such as CNS ,where herpes
virus may
cause meningitis or encephalitis
.
Typical secondary sites of
localization
A-skin:
Viremia can result in a rash due
to
infection of cells in the
epithelium .This type of rash
contains
infectious virus.
B-Central Nervous system
The most common route by
which viruses
infect the CNS is one whereby
viruscarried by the blood-infects
endothelial
cells of the cerebral vessels , and
ultimately
is released into the brain itself
• Alternatively ,virus can
be
released from endothelial
cells
into the cerebrospinal
fluid at the
choroid plexus .A less
common
,but important route of
viral
spread is the axonal
migration of
virus from peripheral
nerve
endings directly into the
CNS
(Rabies virus)
5- fetus
-The fetus represents a special ,but
very important
important ,site for secondary
localization of
virus infections.
-virus from the maternal circulation
infects cells of
of the placenta ,thereby gaining
access to the
fetal circulation and to all of the
tissues of the
developing fetus
- Neonatal infection can also occur
during birth
when the fetus comes in contact
with infected
genital secretions of the mother.
Primary and Secondary
Infection
• Some viruses remain
localized and
cause disease at the primary
site of
infection
• Viruses can disseminated
through out
the body ,and infect cells at
secondary
sites characteristic for each
specific
virus type , thus causing the
disease
typically associated with that
species .
• the presence of virus in the
blood is
Cell Tropism
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.

Physical barriers.
Local temperature, pH, and oxygen tension
enzymes and
non-specific factors in body secretions.
Digestive enzymes and bile in the

gastrointestinal tract that

may inactivate some viruses.

Cell Damage
 Viruses may replicate widely throughout the
body without any
disease symptoms if they do not cause
significant cell damage
or death.
Retroviruses do not generally cause cell

death, being released

from the cell by budding rather than by cell
lysis, and cause
persistent infections.
Conversely, Picornaviruses cause lysis and

death of the cells

in which they replicate, leading to fever and
increased mucus
secretion .in the case of Rhinoviruses,
paralysis or death
(usually due to respiratory failure) for
Poliovirus.
Factors Involved in
Termination of
The Acute Infection
• In a typical uncomplicated
,acute
infection ,virus is totally
eliminated
from the host in two to three
weeks
.This outcome is primarily a
function
of the host’s immune system
, with
involvement of both cell-
mediated
and humoral responses .
• The relative importance of
these two
responses depends upon the
virus
A- cell mediated responses
• the earliest immune system responses
to virus
infection are a generalized
inflammatory response
,accompanied by nonspecific killing of
infected
cells by natural killer cells .
• This latter activity is enhanced by
interferon and
other cytokines and begins well before
the virus –
specific immune response.
• Later, cytolysis by virus specific
cytotoxic T
lymphocytes that recognize virus
peptides displayed
on the cell surface ,also eliminates
infected cells
• These cellular responses are especially
significant in
that they help to limit the spread of the
infection
by killing infected cells before they
have released
B-Humoral response
• Circulating antibodies may
be
directed against any of the
virus
protein
• Humoral antibodies also
take part in
killing infected cells by two
mechanism
1-antibody –dependent , cell
–
mediated cytotoxicity
2-complement –mediated
lysis
Viral Clearance or
Persistence
 The majority of viral infections are
cleared but certain
viruses may cause persistent infections.
There are 2
types of chronic persistent infections.
True Latency - the virus remains

completely latent
following primary infection e.g. HSV,
VZV. Its
genome may be integrated into the
cellular genome or
exists as episomes.
Persistence - the virus replicates

continuously in the
body at a very low level e.g. HIV, HBV,
CMV, EBV.
Mechanisms of Viral
Persistence
 antigenic variation
immune tolerance, causing a reduced response to an

antigen, may be due to

genetic factors, pre-natal infection, molecular mimicry
restricted gene expression

down-regulation of MHC class I expression, resulting in lack

of recognition of
infected cells e.g. Adenoviruses
down-regulation of accessory molecules involved in immune

recognition e.g.
by EBV.
infection of immune privilege sites within the body e.g. HSV

in sensory
ganglia in the CNS
direct infection of the cells of the immune system itself e.g.

Herpes viruses,
Retroviruses (HIV) - often resulting in immunosuppression

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