Viral pathogenesis

What does a pathogen have to

do?
Infect(infest) a host
Reproduce (replicate) itself
Ensure that its progeny are
transmitted to another host
Viral pathogenesis is the process by which viruses produce disease in the
host.
The factors that determine the viral transmission, multiplication,
dissemination, and development of disease in the host involve complex
and dynamic interactions between the virus and the susceptible host.
Viruses cause disease when they breach the host's primary physical and
natural protective barriers; evade local, tissue, and immune defenses;
spread in the body; and destroy cells either directly or via bystander
immune and inflammatory responses. Viral pathogenesis comprises of
several stages, including (1) transmission and entry of the virus into the
host, (2) spread in the host, (3) tropism, (4) virulence, (5) patterns of
viral infection and disease, (6) host factors, (7) and host defense.
 Transmission patterns

 Horizontal Transmission: Direct person-to-

person spread.
 Vertical Transmission: Relies on
PERSISTENCE of the agent to transfer
infection from parents to offspring. Several forms
of vertical transmission can be distinguished:
 1.Neonatal infection at birth, e.g. gonorrhorea,
AIDS.
 2.Infection in utero e.g. syphilis, CMV, Rubella
(CRS), AIDS.
 3. Germ line infection - via ovum or sperm.
 Mechanisms of Transmission
 Aerosols - inhalation of droplets, e.g. Rhinoviruses, the 'Common
Cold Virus' or Adenoviruses.
 Faecal-Oral - e.g. Astroviruses, Caliciviruses; these viruses cause
acute gastroenteritis.
 Vector-borne - e.g. in Arthropods such as mosquitos, ticks, fleas:
Arboviruses.
 Close personal contact - especially exchange of bodily fluids: Sex;
Blood, e.g. Herpesviruses
 Vertical transmission; from mother to child
 Iatrogenic. Transmission; due to medical procedures, such as
touching a wound, an injection or transplantation of infected material.
 Percutaneous transmission; exposure through any break in intact
skin, whether from sharps injury (such as from needles, stylets, or
surgical blades) or other types of tissue trauma.
 Entry into the Host

 Skin - dead cells, therefore cannot support virus replication.

Most viruses which infect via the skin require a breach in
the physical integrity of this effective barrier, e.g. cuts or
abrasions. Many viruses employ vectors, e.g. ticks,
mosquitos or vampire bats to breach the barrier.
 Respiratory tract - In contrast to skin, the respiratory tract
and all other mucosal surfaces possess sophisticated
immune defence mechanisms, as well as non-specific
inhibitory mechanisms (cilliated epithelium, mucus
secretion, lower temperature) which viruses must overcome.

 Entry into the Host

Gastrointestinal tract - a hostile

environment; gastric acid, bile salts, etc
Genitourinary tract - relatively less hostile
than the above, but less frequently exposed
to extraneous viruses (?)
Conjunctiva - an exposed site and relatively
unprotected
 Cell/Tissue Tropism
 Tropism - the ability of a virus to replicate in
particular cells or tissues - is controlled partly by
the route of infection but largely by the interaction
of a virus attachment protein (V.A.P.) with a
specific receptor molecule on the surface of a cell,
and has considerable effect on pathogenesis. Many
V.A.P.'s and virus receptors are now known.
 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 for
Poliovirus.
 Cellular Pathogenesis
 Cells can respond to viral infections in 3 ways: (1) No apparent
change, (2) Death, and (3) Transformation
 Direct cell damage and death from viral infection may result from
 diversion of the cell's energy
 shutoff of cell macromolecular synthesis
 competition of viral mRNA for cellular ribosomes
 competition of viral promoters and transcriptional enhancers for
cellular transcriptional factors such as DNA polymerases
 Indirect cell damage can result from
 integration of the viral genome
 induction of mutations in the host genome
 host immune response.
 Mechanisms of viral cytopathogenesis
Inhibition of cellular protein
synthesis
Inhibition and degradation of
cellular DNA
Alteration of cell membrane
structure
Glycoprotein insertion
Syncytia formation
Disruption of cytoskeleton
permeability
Inclusion bodies
Toxicity of Virion components
Polioviruses, HSV,
poxviruses, togaviruses
herpesviruses
All enveloped viruses
HSV, VZ virus, HIV
HSV, naked viruses
Togaviruses,
herpesviruses
Rabies
Adenovirus fibers
 Overall fate of the cell
 The cell dies in cytocidal infections
this may be acute (when infection is brief and
self-limiting) or chronic (drawn out, only a few
cells infected while the rest proliferate)-
Cytocidal effect
 The cell lives in persistent infections
this may be productive or nonproductive (refers
to whether or not virions are produced) or it may
alternate between the two by way of latency and
reactivation - Steady state infection
 Special cases

 Transformation-Integrated infection
(Viruses and Tumor)
 Apoptosis
 Course of Viral Infection

Primary Replication

 Having gained entry to a potential host, the

virus must initiate an infection by entering a
susceptible cell. This frequently determines
whether the infection will remain localized at
the site of entry or spread to become a
systemic infection
 Localized Infections
Viruses Primary
Replication

Rhinoviruses U.R.T.
Rotaviruses Intestinal
epithelium
Papillomaviruses Epidermis
 Systemic Infections
Virus Primary Replication Secondary Replication

Enteroviruses
Intestinal epithelium Lymphoid
tissues, C.N.S.
Herpesviruses
Oropharynx or Lymphoid cells,
G.U.tract C.N.S.
 SYSTEMIC SPREAD
3 main mechanisms for spread of
viruses throughout the host:
direct cell-cell contact
via the bloodstream
via the nervous system
 via the bloodstream
 Virus may get into the bloodstream by direct
inoculation - e.g. Arthropod vectors, blood
transfusion or I.V. drug abuse. The virus may
travel free in the plasma (Togaviruses,
Enteroviruses), or in association with red cells
(Orbiviruses), platelets (HSV), lymphocytes (EBV,
CMV) or monocytes (Lentiviruses). Primary
viraemia usually proceeds and is necessary for
spread to the blood stream, followed by more
generalized, higher titre secondary viraemia as
the virus reaches other target tissues or replicates
directly in blood cells
 Via Cell to cell
Spread via tight junctions is common for viruses that

infect epithelial layers.

Retroviruses and other immunotropic viruses often utilize

immunological synapses for cell-to-cell spread.

The fusion of membranes from adjacent cells results in

multi-nucleated giant cells, also called syncytia.

 via the nervous system
 spread to nervous system is preceded by primary
viraemia.
 In some cases, spread occurs directly by contact
with neurons at the primary site of infection, in
other cases via the bloodstream.
 Once in peripheral nerves, the virus can spread to
the CNS by axonal transport along neurons (classic
- HSV).
 Viruses can cross synaptic junctions since these
frequently contain virus receptors, allowing the
virus to jump from one cell to another
 Secondary Replication
Occurs in systemic infections when a
virus reaches other tissues in which
it is capable of replication, e.g.
Poliovirus (gut epithelium - neurons
in brain & spinal cord) or Lentiviruses
(macrophages - CNS + many other
tissues).
If a virus can be prevented from
reaching tissues where secondary
replication can occur, generally no
disease results.
:

Localized Infections:
Virus: Primary Replication:
Rhinoviruses U.R.T.
Rotaviruses Intestinal epithelium
Papillomavirus
Epidermis
es
Systemic Infections:
Secondary
Virus: Primary Replication:
Replication:
Lymphoid tissues,
Enteroviruses Intestinal epithelium
C.N.S.
Oropharynx or
Herpesviruses Lymphoid cells, C.N.S.
G.U.tract
Incubation periods of viral infections
Influenza 1-2d Chickenpox 13-17d

Common cold 1-3d Mumps 16-20d

Bronchiolitis,croup 3-5d Rubella 17-20d

Acute respiratory 5-7d Mononucleosis 30-50d

disease
Dengue 5-8d Hepatitis A 15-40d

Herpes simplex 5-8d Hepatitis B 50-150d

Enteroviruses 6-12d Rabies 30-100d

poliomyelitis 5-20d Papilloma 50-150d

Measles 9-12d HIV 1-10y

Types of Infection
 Inapparent infection( Subclinical
infection) .
 Apparent infection:
 Acute infection
 Persistent Infection

Chronic infections
Latent Infection
Slow virus infections
 Acute Infection
 Recovery with no residue effects
 Recovery with residue effects e.g. acute viral encephalitis
leading to neurological sequelae.
 Death
 Proceed to chronic infection
 Chronic Infection
 Silent subclinical infection for life e.g. CMV, EBV
A long silent period before disease e.g. HIV, SSPE, PML
 Reactivation to cause acute disease e.g. herpes and
shingles.
 Chronicdisease with relapses and excerbations e.g.
HBV, HCV.
 Persistence
Long term persistence of virus results
from two main mechanisms:
 a) Regulation of lytic potential
 b) Evasion of immune surveillance
Chronic Infection
Viruscan be continuously
detected ; mild or no clinical
symptoms may be evident.
Latent infection
The Virus persists in an occult, or cryptic,
from most of the time. There will be
intermittent flare-ups of clinical disease ,
Infectious virus can be recovered during
flare-ups . Latent virus infections typically
persist for the entire life of the host
Slow virus infection
A prolonged incubation period, lasting
months or years, daring which virus
continues to multiply. Clinical symptoms
are usually not evident during the long
incubation period .
Types of Viral infections at the cellular level
Type Virus production Fate of cell
Abortive - No effect
Cytolytic + Death
Persistent
Productive + Senescence
Latent - No effect
Transforming
DNA viruses - Immortalization
RNA viruses + Immortalization
 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. LFA-3 and ICAM-1 by EBV.
infection of immuno-priviliged 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.